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Younossi, Z. M. etal. Global epidemiology of nonalcoholic fatty liver disease\ - Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 64, 73 84 \(2016\).\r:70)/F 4/H/N/Rect[294.757 697.855 299.987 685.444]/Subtype/Link/Type/Annot>> endobj 4 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:16. Younossi, Z. M. etal. Global epidemiology of nonalcoholic fatty liver diseas\ e- Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 64, 73 84 \(2016\).\r:71)/F 4/H/N/Rect[287.983 664.855 293.186 652.444]/Subtype/Link/Type/Annot>> endobj 5 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:12. Friedman, S. L., Neuschwander- Tetri, B. A., Rinella, M. & Sanyal, A. J. Me\ chanisms of NAFLD development and therapeutic strategies. Nat. Med. 24, 908 922 \(2018\).\r:72)/F 4/H/N/Rect[233.659 576.855 238.645 564.444]/Subtype/Link/Type/Annot>> endobj 6 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:6. Eslam, M., Sanyal, A. J. & George, J., International Consensus Panel. MAFLD: \ a consensus- driven proposed nomenclature for metabolic associated fatty liver disease. Gastroenterology 158, 1999 2014.e1 \(\ 2020\).\r:73)/F 4/H/N/Rect[176.44 554.855 178.977 542.444]/Subtype/Link/Type/Annot>> endobj 7 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:17. Angulo, P. etal. Liver fibrosis, but no other histologic features, is associa\ ted with long- term outcomes \nof patients with nonalcoholic fatty liver disease. Gastroenterology 149, 389 397.e10 \(2015\).\ \r:74)/F 4/H/N/Rect[296.642 543.855 301.746 531.444]/Subtype/Link/Type/Annot>> endobj 8 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:18. Ekstedt, M. etal. Fibrosis stage is the strongest predictor for disease- spec\ ific mortality in NAFLD \nafter up to 33 years of follow- up. Hepatology 61, 1547 1554 \(2015\).\r:75)/F 4/H/N/Rect[302.946 543.855 308.05 531.444]/Subtype/Link/Type/Annot>> endobj 9 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:19. Pais, R. etal. NAFLD and liver transplantation: current burden and expected c\ hallenges. J. Hepatol. 65, 1245 1257 \(2016\).\r:76)/F 4/H/N/Rect[312.032 521.855 317.123 509.444]/Subtype/Link/Type/Annot>> endobj 10 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:20. Segovia- Miranda, F. etal. Three- dimensional \nspatially resolved geometrical\ and functional \nmodels of human liver tissue reveal new aspects \nof NAFLD progression. Nat. Med. 25, 1885 1893 \(2019\).\r\ :77)/F 4/H/N/Rect[334.766 389.855 339.761 377.444]/Subtype/Link/Type/Annot>> endobj 11 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:21. Harrison, S. A. etal. A blood- based biomarker panel \(NIS4\) for non- invasiv\ e diagnosis of non- alcoholic steatohepatitis and liver fibrosis: a prospective derivation and global validation study. Lancet \ Gastroenterol. Hepatol. 5, 970 985 :78)/F 4/H/N/Rect[327.06 345.855 332.055 333.444]/Subtype/Link/Type/Annot>> endobj 12 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:24. Srivastava, A. etal. Prospective evaluation of a primary care referral pathwa\ y for patients with non- alcoholic fatty liver disease. J. Hepatol. 71, 371 378 \(2019\).\r:79)/F 4/H/N/Rect[334.766 345.855 339.761 333.444]/Subtype/Link/Type/Annot>> endobj 13 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:Fig. 1 | Contributing factors in NAFLD progression and NASH pathogenesis. No\ n- alcoholic fatty liver disease \(NAFLD\) is a progressive disease that starts with simple steatosis \(non- alcoholic fatty live\ r \(NAFL\)\) and can evolve to a more comp:80)/F 4/H/N/Rect[223.102 191.855 227.607 179.444]/Subtype/Link/Type/Annot>> endobj 14 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:25. Donnelly, K. L. etal. Sources of fatty acids stored \nin liver and secreted vi\ a lipoproteins in patients with nonalcoholic fatty liver disease. J. Clin. Invest. 115, 1343 1351 \(2005\).\r:81)/F 4/H/N/Rect[217.244 70.8547 222.541 58.4439]/Subtype/Link/Type/Annot>> endobj 15 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:26. Softic, S., Cohen, D. E. & Kahn, C. R. Role of dietary fructose and hepatic de\ novo lipogenesis in fatty liver disease. Dig. Dis. Sci. 61, 1282 1293 \(2016\).\r:82)/F 4/H/N/Rect[226.403 59.8547 231.702 47.4439]/Subtype/Link/Type/Annot>> endobj 16 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:Box 1 | Mouse models of fatty liver disease\rMultiple mouse models have been genera\ ted to study non- alcoholic fatty liver disease \(NAFLD\) and the transition of non- alcoholic steatohepatitis \(NASH\) to hepato\ cellular carcinoma \(HCC\). The strong ass:83)/F 4/H/N/Rect[371.68 719.855 376.216 707.444]/Subtype/Link/Type/Annot>> endobj 17 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:27. Todoric, J. etal. Fructose stimulated denovo lipogenesis is promoted by infl\ ammation. Nat. Metab. 2, 1034 1045 \(2020\).\r:84)/F 4/H/N/Rect[376.505 686.855 381.649 674.444]/Subtype/Link/Type/Annot>> endobj 18 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:27. Todoric, J. etal. Fructose stimulated denovo lipogenesis is promoted by inf\ lammation. Nat. Metab. 2, 1034 1045 \(2020\).\r:85)/F 4/H/N/Rect[468.813 642.855 473.945 630.444]/Subtype/Link/Type/Annot>> endobj 19 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:28. Nakagawa, H. etal. ER stress cooperates with hypernutrition to trigger TNF- d\ ependent spontaneous HCC development. Cancer Cell 26, 331 343 \n\(2014\). \nThis study shows how hepatic endoplasmic reticulu\ m stress, hepatocyte cell death \nand in:86)/F 4/H/N/Rect[376.678 587.855 381.765 575.444]/Subtype/Link/Type/Annot>> endobj 20 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:29. Ichimura, M. etal. High- fat and high- cholesterol diet rapidly induces non- \ alcoholic steatohepatitis with advanced fibrosis in Sprague- Dawley rats. Hepatol. Res. 45, 458 469 \(2015\).\r:87)/F 4/H/N/Rect[510.807 543.855 515.903 531.444]/Subtype/Link/Type/Annot>> endobj 21 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:30. Savard, C. etal. Synergistic interaction of dietary cholesterol and dietary f\ at in inducing experimental steatohepatitis. Hepatology 57, 81 92 \(2013\).\r:88)/F 4/H/N/Rect[517.099 543.855 522.194 531.444]/Subtype/Link/Type/Annot>> endobj 22 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:31. Liang, J. Q. etal. Dietary cholesterol promotes steatohepatitis related hepat\ ocellular carcinoma through dysregulated metabolism and calcium signaling. Nat. Commun. 9, 4490 \(2018\).\r:89)/F 4/H/N/Rect[450.321 532.974 455.564 520.444]/Subtype/Link/Type/Annot>> endobj 23 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:32. Zhang, X. etal. Dietary cholesterol drives fatty \nliver- associated liver can\ cer by modulating gut microbiota and metabolites. Gut 70, 761 774 \(2021\).\r:90)/F 4/H/N/Rect[456.834 532.974 462.078 520.444]/Subtype/Link/Type/Annot>> endobj 24 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:33. Kim, J. Y. etal. ER stress drives lipogenesis and steatohepatitis via Caspase\ -2 activation of S1P. \nCell 175, 133 145.e15 \(2018\). \nThis study shows that caspase 2-mediated regulation of SREBP has a \ crucial impact on NASH development.\r:91)/F 4/H/N/Rect[431.721 477.855 437.009 465.444]/Subtype/Link/Type/Annot>> endobj 25 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:33. Kim, J. Y. etal. ER stress drives lipogenesis and steatohepatitis via Caspas\ e-2 activation of S1P. \nCell 175, 133 145.e15 \(2018\). \nThis study shows that caspase 2-mediated regulation of SREBP has a\ crucial impact on NASH development.\r:92)/F 4/H/N/Rect[502.109 444.974 507.163 432.444]/Subtype/Link/Type/Annot>> endobj 26 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:34. Imajo, K. etal. Hyperresponsivity to low- dose endotoxin during progression t\ o nonalcoholic steatohepatitis is regulated by leptin- mediated signaling. Cell Metab. 16, 44 54 \(2012\).\r:93)/F 4/H/N/Rect[373.098 356.855 378.116 344.444]/Subtype/Link/Type/Annot>> endobj 27 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:35. Tran, S. etal. Impaired Kupffer cell self- renewal alters the liver response \ to lipid overload during non- alcoholic steatohepatitis. Immunity 53, 627 640.e5 \(2020\). \nThis study shows that monocyte- \ derived Kupffer cells are generated du:94)/F 4/H/N/Rect[387.945 334.855 393.063 322.444]/Subtype/Link/Type/Annot>> endobj 28 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:36. Feldstein, A. E. etal. Hepatocyte apoptosis and \nfas expression are prominent\ features of human nonalcoholic steatohepatitis. Gastroenterology 125, 437 443 \(2003\).\r:95)/F 4/H/N/Rect[418.531 301.855 423.624 289.444]/Subtype/Link/Type/Annot>> endobj 29 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:37. Schwabe, R. F. & Luedde, T. Apoptosis and necroptosis in the liver: a matter o\ f life and death. Nat. Rev. Gastroenterol. Hepatol. 15, 738 752 \(2018\).\r:96)/F 4/H/N/Rect[473.588 279.855 478.669 267.444]/Subtype/Link/Type/Annot>> endobj 30 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:38. Luedde, T. etal. Deletion of NEMO/IKK in liver parenchymal cells causes stea\ tohepatitis and hepatocellular carcinoma. Cancer Cell 11, 119 132 \(2007\).\r:97)/F 4/H/N/Rect[513.306 224.855 518.402 212.444]/Subtype/Link/Type/Annot>> endobj 31 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:38. Luedde, T. etal. Deletion of NEMO/IKK in liver parenchymal cells causes ste\ atohepatitis and hepatocellular carcinoma. Cancer Cell 11, 119 132 \(2007\).\r:98)/F 4/H/N/Rect[545.399 213.855 550.658 201.444]/Subtype/Link/Type/Annot>> endobj 32 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:28. Nakagawa, H. etal. ER stress cooperates with hypernutrition to trigger TNF- \ dependent spontaneous HCC development. Cancer Cell 26, 331 343 \n\(2014\). \nThis study shows how hepatic endoplasmic reticul\ um stress, hepatocyte cell death \nand i:99)/F 4/H/N/Rect[398.65 125.855 403.745 113.444]/Subtype/Link/Type/Annot>> endobj 33 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:39. Zhao, P. etal. An AMPK- caspase-6 axis controls liver damage in nonalcoholic \ steatohepatitis. Science 367, 652 660 \(2020\). \nThis study shows the crucial role of the \nAMPK caspase 6 axis in NASH path\ ogenesis.\r:100)/F 4/H/N/Rect[388.34 81.8547 393.689 69.4439]/Subtype/Link/Type/Annot>> endobj 34 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:39. Zhao, P. etal. An AMPK- caspase-6 axis controls liver damage in nonalcoholic\ steatohepatitis. Science 367, 652 660 \(2020\). \nThis study shows the crucial role of the \nAMPK caspase 6 axis in NASH pat\ hogenesis.\r:101)/F 4/H/N/Rect[425.85 59.8547 430.946 47.4439]/Subtype/Link/Type/Annot>> endobj 35 0 obj <>/ExtGState<>/Font<>/ProcSet[/PDF/Text]/XObject<>>> endobj 36 0 obj <>stream x}#G.=ÊgY0Mnsn$PȬd l֘^B1oWU"9矻?|Oo3pm&^ow7_7;,+xwrZ]ݧ~_7OyU,,E[˶"ۛ?͎zYϞy&:1#q?~^v/&ߒi^Bw>q%{Q|0U.l5{|-d5{M<>j5Y TUYVr 3wl1bex͂^0-'l|6v \M%4Y&{h]8wt˲,:i~3~;'eIUSͲ̺6&T!Ui5`gGaz/Z9]m7v,(a|\naM>[OE&y.>jgjzCEٗ \M5"rv7_ %3\~7W;4LXLxdUמ,a+Ù,X\QXXVy{HO 54neٔr@=X\Mre5}ɶ*sxnf{}4(͋M­\Vf\6V1+J62A/# P⻚:u A cq7tZout ˉG9Óހi[v)}N(˙\"(Ezd1 j.pUwR:ȥ/~o=xgP(9tɽE2n&H6ք@CUg;1?N[dND58xd#χzv)%mMAecdD_Qt5N@c ސÎ&u8w luu3ei>|bHdwZc"q7pĄ iaX.ɻd/ AÐ싯}퉚dyOsC>)kBHԨv}c>BADCW}q%KQo6Rn< [o: (ljuPGvze 518Tz ojnJJ-T#*.4:TMw4ûjSlo3N,e&{{ǶqdALiN4n-X{WO|:7>QO\So6OmYX6CVCI{"-|=W+͌#EE.ER˭"PbfDh/Rָ]wx^M=M(V5/4PJbHB+o/m F@M/ ːqx g,rUz-Z;BZd[hX2cu b\Q 1} δ?:g,IhpEeִNu4SQݎ7%YY5yfg=V8f(I ї)oOpzv #iaCr,H3ZV@@r9$lc͕4Y0'{y$m>N;FRR*2ئZy+e(3`.QH/ƹW_r^ fMµv+2Gᅲ==W71{oq@y9Qka =WRdD|Vp/Oׯn4+`28kՄ0>ХR* \!K*KآjGo^k:kR}#Ygq|䕲[n{NT"Z*jB⑎2~K RAAWdj`&JݷjqH? r7ͤ!o!5Z`$LU81LiMx1: 069Z COYdRݼǎI~ثU/Bԕ4$Ҁ:ke6]4rU>p CZS[(zT Y^&d5)b>G*Y`\7}רw+){.h)1%BW?Qb pA^BolWdi@'8E@/ZV6"Hym>I5f;6hXvenţqHomS+[֑F(hC@ʬTGiUSF|NXʡ ɵs`o!#([9[ ###{.#ۥl1+oZb¡|nEERVr|=)+;KkVi,5b87Ѡ XG:'#UĞ96s\^CX*iն;v1\:}H6*s_, l,T(#[l<edCg8b BVv؅rMC[pJepR/~?GP=WsqrxjeZ--3x̬qK04i0^!v|)߀7ZxZgۯMK Eu+X_Dv` b0eqψZVzE(].-؈Aq ֧To5X^hLi Fd^}_|R2Uif(hRHBfVqKYU{�J'EL|-ƃ f[_܆GkuV#V}^ZSF{hB'wDv{8;sy `:h-{3_E֓ة5>i*bՇ2ϰ>iI~N&䖀B()!9H1YGDV \)?]>LQrpHVW JlCߢF%pK~-l.rQv%-U-Ev M-e/~*qWkbVT1Y6c,/v$F#T=Xڹ X_P[מ#ƥfr#舻c=%9Kޜ_2!Iظ~W=rO`v%} LX`X%[~஡$h/}^L[6iў(Pަ4[ZPHVh1~ CY=)B]Ě]ruH _J+=(o#D?UB1t Ӗ-5@u4[z/"j8rk+x[ţ4qߜx;v#Np'0=J4gW;5 &pS85̝uT44qOCXON*Pް;_Q8k,x\b8CtVz2zg`)|VA?;U*MF{?%lQzQִb?EUe;[=}?~x>NY_}v"ʑQ-bjdbU}U_Cǘl7hL葈aT%õB'n}/ ,.^9 uȨTzs{,4\db̬{: a1C?ACF4++k,.0)F|+A"'$a>=P_cL %h ~!+lCܪϞs L>m]}AM YN.ر@{qZ{>ni`ăI<;H7[~U#BTi]4N]"nqG*9BH\٭B;BhŒ6Iz"Q q@BBj?XiNRǔKt9D[j9E^+#a=P~I:Al8Ep.FXSj!U*k2ѨRI,5A~_;p䧱+;gGډ065s AB]Nq[_l4.ƕi1͍MnKs̳ᑇ#[T "{eDI3'=Sg-3 -QSmWugM vC vZkR5hpFFd(6hktOs:Rq9+À'/Xt$QՀ┐"'sav^|^ 9>7/ ]ϫ-fM,_<4/g^J!p0ʵ@;?? =Qp훒tˮwq'9S JU`.p|7RdP"a1ںrP]<It8TpD$V\ ; n~We+Ly yx xb,>p!+I'JT B&Ec0Bԋ0)Jˀlb4^cK@ֆX0An~l)P7jAHҾ+|ͅvT9)_A;PmWeHE1|T s4ir!:e%CC{&TʵYhmĺcZZ/b7@h947/Ig'v|jLC)l S3%L&IWʡd:wtnѹc-N< IaIߎx{y3GԜuN> 7^WEuBWRlpKZp4SKOĖEo&ò(}U, cKc~gL-Tδ:v7_C&E:ucH{"F3du3rTD&d,+q@!yqx'd$3zz+zY$~J )њ뤏,38>?z8o(idR5-7%Zsx[6MKzTOkG&M9bUUef2+2Mew7+Pe񃧟i8>E.8H&9 Y@4W@gұ)0 9u3$XżTm4?OYe UTO`Xkg~w0tdT98I5Dv:vfIl0q.>;3ȇh?9΅oo#}~QE M۶ SAy/m6wXJ/0wC[f^ʵv>_IqVR.dA bt"$zi īx*ԨюfC/z{Z( ^=p@ k MဂL23T em)p $Mt0%f I)"YGq M88uBx~7WT[{rxΖeU;l1W/Lu*_*2Q\Lj ig *rE%)H|erLmo$\E\ Xׂ! 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ȺaRL<RaK ,r& +|s>/ExtGState<>/Font<>/ProcSet[/PDF/Text]/XObject<<>>>> endobj 38 0 obj <>stream x%O@ SL'ǽmA؅ b?Jy /a4Tcatvq&ڬ2Ɍ:bۏm$/9$3 endstream endobj 39 0 obj <> endobj 40 0 obj [41 0 R 42 0 R 43 0 R 44 0 R 45 0 R 46 0 R 47 0 R 48 0 R 49 0 R 50 0 R 51 0 R 52 0 R] endobj 41 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:39. Zhao, P. etal. An AMPK- caspase-6 axis controls liver damage in nonalcoholi\ c steatohepatitis. Science 367, 652 660 \(2020\). \nThis study shows the crucial role of the \nAMPK caspase 6 axis in NASH pa\ thogenesis.\r:102)/F 4/H/N/Rect[175.691 235.855 180.803 223.444]/Subtype/Link/Type/Annot>> endobj 42 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:40. Barreyro, F. J. etal. The pan- caspase inhibitor Emricasan \(IDN-6556\) decrea\ ses liver injury and fibrosis in a murine model of non- alcoholic steatohepatitis. Liver Int. 35, 953 966 \(2015\).\r:103)/F 4/H/N/Rect[224.716 224.855 229.969 212.444]/Subtype/Link/Type/Annot>> endobj 43 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:41. Witek, R. P. etal. Pan- caspase inhibitor VX-166 reduces fibrosis in an anima\ l model of nonalcoholic steatohepatitis. Hepatology 50, 1421 1430 \n\(2009\).\r:104)/F 4/H/N/Rect[231.244 224.855 236.497 212.444]/Subtype/Link/Type/Annot>> endobj 44 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:42. Wandrer, F. etal. TNF- Receptor-1 inhibition reduces liver steatosis, hepatoc\ ellular injury and fibrosis in NAFLD mice. Cell Death Dis. 11, 212 \(2020\).\r:105)/F 4/H/N/Rect[234.714 180.855 239.81 168.444]/Subtype/Link/Type/Annot>> endobj 45 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:43. Arroyave- Ospina, J. C., Wu, Z., Geng, Y. & \nMoshage, H. Role of oxidative str\ ess in the pathogenesis of non- alcoholic fatty liver disease: implications for prevention and therapy. Antioxidants 10, 17\ 4 \(2021\).\r:106)/F 4/H/N/Rect[328.314 136.855 333.433 124.444]/Subtype/Link/Type/Annot>> endobj 46 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:44. Chen, Z., Tian, R., She, Z., Cai, J. & Li, H. Role of oxidative stress in the \ pathogenesis of nonalcoholic fatty liver disease. Free Radic. Biol. Med. 152, \n116 141 \(2020\).\r:107)/F 4/H/N/Rect[334.641 136.855 339.761 124.444]/Subtype/Link/Type/Annot>> endobj 47 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:45. Meakin, P. J. etal. Susceptibility of Nrf2-null mice \nto steatohepatitis and \ cirrhosis upon consumption \nof a high- fat diet is associated with oxidative stress, perturbation of the unfolded protein respo\ nse, and disturbance in the expression:108)/F 4/H/N/Rect[334.655 92.8547 339.761 80.4439]/Subtype/Link/Type/Annot>> endobj 48 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:38. Luedde, T. etal. Deletion of NEMO/IKK in liver parenchymal cells causes st\ eatohepatitis and hepatocellular carcinoma. Cancer Cell 11, 119 132 \(2007\).\r:109)/F 4/H/N/Rect[215.335 59.8547 220.43 47.4439]/Subtype/Link/Type/Annot>> endobj 49 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:46. Grohmann, M. etal. Obesity drives STAT-1-dependent NASH and STAT-3-dependent \ HCC. Cell 175, \n1289 1306.e20 \(2018\). \nThis study shows how oxidative stress independently modulates signalling pathways \ to promote NASH, fibrosis and HCC devel:110)/F 4/H/N/Rect[419.164 235.974 424.204 223.444]/Subtype/Link/Type/Annot>> endobj 50 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:46. Grohmann, M. etal. Obesity drives STAT-1-dependent NASH and STAT-3-dependent\ HCC. Cell 175, \n1289 1306.e20 \(2018\). \nThis study shows how oxidative stress independently modulates signalling pathways\ to promote NASH, fibrosis and HCC deve:111)/F 4/H/N/Rect[514.358 191.855 519.453 179.444]/Subtype/Link/Type/Annot>> endobj 51 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:47. Mar, M. etal. Mitochondrial free cholesterol loading sensitizes to TNF- and \ Fas- mediated steatohepatitis. Cell Metab. 4, 185 198 \(2006\).\r:112)/F 4/H/N/Rect[390.339 147.855 395.686 135.444]/Subtype/Link/Type/Annot>> endobj 52 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:48. Brenner, C., Galluzzi, L., Kepp, O. & Kroemer, G. Decoding cell death signals \ in liver inflammation. \nJ. 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Ramachandran, P. etal. Resolving the fibrotic niche \nof human liver cirrhosis\ at single- cell level. Nature 575, 512 518 \(2019\). \nThis study reveals the immune landscape of human cirrhosis using sin\ gle- cell RNA sequencing.\r:176)/F 4/H/N/Rect[261.049 730.855 266.193 718.444]/Subtype/Link/Type/Annot>> endobj 1878 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:81. Remmerie, A. etal. Osteopontin expression identifies a subset of recruited\ macrophages distinct from Kupffer cells in the fatty liver. Immunity 53, \n641 657.e14 \(2020\). \nThis study highlights mac\ rophage diversity in a mouse model of N:177)/F 4/H/N/Rect[265.195 697.855 270.367 685.444]/Subtype/Link/Type/Annot>> endobj 1879 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:83. Ramachandran, P. etal. Resolving the fibrotic niche \nof human liver cirrhosi\ s at single- cell level. Nature 575, 512 518 \(2019\). \nThis study reveals the immune landscape of human cirrhosis using si\ ngle- cell RNA sequencing.\r:178)/F 4/H/N/Rect[273.168 697.855 278.341 685.444]/Subtype/Link/Type/Annot>> endobj 1880 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:Fig. 3 | Immune modulation of NASH pathogenesis. The hepatic immune cell rep\ ertoire is reshaped during non- alcoholic steatohepatitis \(NASH\) and participates in the uncontrolled inflammatory environment \ that promotes liver injury \(hepatocyte:179)/F 4/H/N/Rect[210.606 587.855 215.157 575.444]/Subtype/Link/Type/Annot>> endobj 1881 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:Box 2 | Crosstalk between immune and parenchymal cells during NASH\rVarious immune \ cell subsets affect different aspects of the pathogenesis of non- alcoholic steatohepatitis \(NASH\), including liver steatosis,\ inflammation, injury \nand fibrosis. 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Immunol. 186, 26 31 \(2018\).\r:188)/F 4/H/N/Rect[284.229 477.855 289.271 465.444]/Subtype/Link/Type/Annot>> endobj 1885 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:87. Bruzz, S. etal. B2-Lymphocyte responses to oxidative stress- derived antigen\ s contribute to the evolution of nonalcoholic fatty liver disease \(NAFLD\). Free Radic. Biol. Med. 124, 249 259 \(2018\).\r:\ 189)/F 4/H/N/Rect[201.691 433.855 206.791 421.444]/Subtype/Link/Type/Annot>> endobj 1886 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:88. Barrow, F. etal. Microbiota- driven activation of intrahepatic B cells aggrav\ ates nonalcoholic steatohepatitis through innate and adaptive signaling. Hepatology 74, 704 722 \(2021\). \nThis study shows\ that hepatic B cells are activated in :190)/F 4/H/N/Rect[324.013 389.855 329.246 377.444]/Subtype/Link/Type/Annot>> endobj 1887 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:88. Barrow, F. etal. Microbiota- driven activation of intrahepatic B cells aggra\ vates nonalcoholic steatohepatitis through innate and adaptive signaling. Hepatology 74, 704 722 \(2021\). \nThis study show\ s that hepatic B cells are activated in:191)/F 4/H/N/Rect[179.894 345.855 184.989 333.444]/Subtype/Link/Type/Annot>> endobj 1888 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:88. Barrow, F. etal. Microbiota- driven activation of intrahepatic B cells aggr\ avates nonalcoholic steatohepatitis through innate and adaptive signaling. Hepatology 74, 704 722 \(2021\). \nThis study sho\ ws that hepatic B cells are activated i:192)/F 4/H/N/Rect[168.914 323.855 174.01 311.444]/Subtype/Link/Type/Annot>> endobj 1889 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:84. De Silva, N. S. & Klein, U. Dynamics of B cells in germinal centres. Nat. Re\ v. Immunol. 15, 137 148 \(2015\).\r:193)/F 4/H/N/Rect[184.533 268.855 190.149 256.444]/Subtype/Link/Type/Annot>> endobj 1890 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:89. Baumgarth, N. The double life of a B-1 cell: self- reactivity selects for prot\ ective effector functions. \nNat. Rev. Immunol. 11, 34 46 \(2011\).\r:194)/F 4/H/N/Rect[246.554 235.855 251.605 223.444]/Subtype/Link/Type/Annot>> endobj 1891 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:87. Bruzz, S. etal. B2-Lymphocyte responses to oxidative stress- derived antige\ ns contribute to the evolution of nonalcoholic fatty liver disease \(NAFLD\). Free Radic. Biol. Med. 124, 249 259 \(2018\).\r\ :195)/F 4/H/N/Rect[159.855 213.855 164.932 201.444]/Subtype/Link/Type/Annot>> endobj 1892 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:90. Schiemann, B. etal. An essential role for BAFF in \nthe normal development of \ B cells through a BCMA- independent pathway. Science 293, 2111 2114 \(2001\).\r:196)/F 4/H/N/Rect[169.583 158.855 174.679 146.444]/Subtype/Link/Type/Annot>> endobj 1893 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:91. Miyake, T. etal. B cell- activating factor is associated with the histologica\ l severity of nonalcoholic fatty liver disease. Hepatol. Int. 7, 539 547 \(2013\).\r:197)/F 4/H/N/Rect[277.378 147.855 282.62 135.444]/Subtype/Link/Type/Annot>> endobj 1894 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:87. Bruzz, S. etal. B2-Lymphocyte responses to oxidative stress- derived antig\ ens contribute to the evolution of nonalcoholic fatty liver disease \(NAFLD\). Free Radic. Biol. Med. 124, 249 259 \(2018\).\r\ :198)/F 4/H/N/Rect[315.341 136.855 320.436 124.444]/Subtype/Link/Type/Annot>> endobj 1895 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:73. Moro- Sibilot, L. etal. Mouse and human liver contain immunoglobulin A- secr\ eting cells originating from peyer s patches and directed against intestinal antigens. Gastroenterology 151, 311 323 \(2016\)\ .\r:199)/F 4/H/N/Rect[307.379 92.8547 312.474 80.4439]/Subtype/Link/Type/Annot>> endobj 1896 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:92. Shalapour, S. etal. Inflammation- induced IgA+ cells dismantle anti- liver \ cancer immunity. Nature 551, 340 345 \(2017\). \nThis study shows that IgA is a crucial factor in NASH- induced HCC in mice\ .\r:200)/F 4/H/N/Rect[244.472 70.8547 249.908 58.4439]/Subtype/Link/Type/Annot>> endobj 1897 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:93. McPherson, S., Henderson, E., Burt, A. D., Day, C. P. & Anstee, Q. M. Serum im\ munoglobulin levels predict fibrosis in patients with non- alcoholic fatty liver disease. J. 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Merad, M., Sathe, P., Helft, J., Miller, J. & Mortha, A. The dendritic cell li\ neage: ontogeny and function of dendritic cells and their subsets in the steady state and the inflamed setting. Annu. Rev. Immu\ nol. 31, 563 604 \(2013\).\r:204)/F 4/H/N/Rect[399.013 598.855 404.205 586.444]/Subtype/Link/Type/Annot>> endobj 1901 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:94. Merad, M., Sathe, P., Helft, J., Miller, J. & Mortha, A. The dendritic cell l\ ineage: ontogeny and function of dendritic cells and their subsets in the steady state and the inflamed setting. Annu. Rev. Imm\ unol. 31, 563 604 \(2013\).\r:205)/F 4/H/N/Rect[464.624 543.855 469.92 531.444]/Subtype/Link/Type/Annot>> endobj 1902 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:94. Merad, M., Sathe, P., Helft, J., Miller, J. & Mortha, A. The dendritic cell \ lineage: ontogeny and function of dendritic cells and their subsets in the steady state and the inflamed setting. Annu. 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The dendritic cell\ lineage: ontogeny and function of dendritic cells and their subsets in the steady state and the inflamed setting. Annu. Rev. I\ mmunol. 31, 563 604 \(2013\).\r:212)/F 4/H/N/Rect[450.366 290.855 455.606 278.444]/Subtype/Link/Type/Annot>> endobj 1909 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:98. Murphy, K. M. & Stockinger, B. Effector Tcell plasticity: flexibility in the \ face of changing circumstances. Nat. Immunol. 11, 674 680 \n\(2010\).\r:213)/F 4/H/N/Rect[456.874 290.855 462.114 278.444]/Subtype/Link/Type/Annot>> endobj 1910 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:98. Murphy, K. M. & Stockinger, B. Effector Tcell plasticity: flexibility in the\ face of changing circumstances. Nat. Immunol. 11, 674 680 \n\(2010\).\r:214)/F 4/H/N/Rect[529.679 268.855 534.736 256.444]/Subtype/Link/Type/Annot>> endobj 1911 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:99. Luo, X.-Y. etal. IFN-  deficiency attenuates hepatic inflammation and fibros\ is in a steatohepatitis model induced by a methionine- and choline- deficient high- fat diet. Am. J. Physiol. Gastrointest. Liv\ er Physiol. 305, G891 G899 \(2013\).:215)/F 4/H/N/Rect[534.71 158.855 539.978 146.444]/Subtype/Link/Type/Annot>> endobj 1912 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:100. Syn, W.-K. etal. Osteopontin is induced by hedgehog pathway activation and p\ romotes fibrosis progression in nonalcoholic steatohepatitis. 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Progression from nonalcoholic fatty liver to nonalcoholic stea\ tohepatitis is marked by a higher frequency of Th17 cells in the liver and an increased Th17/resting regulatory Tcell ratio in \ peripheral \nblood and in the liver. :225)/F 4/H/N/Rect[334.247 103.855 341.858 91.4439]/Subtype/Link/Type/Annot>> endobj 2794 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:108. Tang, Y. etal. Interleukin-17 exacerbates hepatic steatosis and inflammation\ in non- alcoholic fatty \nliver disease. Clin. Exp. Immunol. 166, 281 290 \(2011\).\r:226)/F 4/H/N/Rect[320.657 92.8547 328.427 80.4439]/Subtype/Link/Type/Annot>> endobj 2795 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:109. Giles, D. A. etal. Regulation of inflammation by \nIL-17A and IL-17F modulate\ s non- alcoholic fatty liver disease pathogenesis. PLoS One 11, e0149783 \(2016\).\r:227)/F 4/H/N/Rect[293.624 70.8547 301.441 58.4439]/Subtype/Link/Type/Annot>> endobj 2796 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:111. Rolla, S. etal. The balance between IL-17 and IL-22 produced by liver- infil\ trating T- helper cells critically controls NASH development in mice. Clin. Sci. 130, 193 203 \(2016\).\r:228)/F 4/H/N/Rect[304.262 70.8547 312.079 58.4439]/Subtype/Link/Type/Annot>> endobj 2797 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:112. Moreno- Fernandez, M. E. etal. PKM2-dependent metabolic skewing of hepatic T\ h17 cells regulates pathogenesis of non- alcoholic fatty liver disease. \nCell Metab. 33, 1187 1204.e9 \(2021\).\r:229)/F 4/H/N/Rect[474.041 730.855 482.073 718.444]/Subtype/Link/Type/Annot>> endobj 2798 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:110. Gomes, A. L. etal. 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Cancer Cell 26, 549 564 \(\ 2014\). \nThis study shows the impact o:241)/F 4/H/N/Rect[465.255 400.855 473.18 388.444]/Subtype/Link/Type/Annot>> endobj 2810 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:117. Wang, T. etal. The immunoregulatory effects \nof CD8 T- cell-derived perforin\ on diet- induced nonalcoholic steatohepatitis. FASEB J. 33, \n8490 8503 \(2019\).\r:242)/F 4/H/N/Rect[466.792 367.855 474.772 355.444]/Subtype/Link/Type/Annot>> endobj 2811 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:118. Matloubian, M. etal. A role for perforin in downregulating T- cell responses\ during chronic \nviral infection. J. Virol. 73, 2527 2536 \(1999\).\r:243)/F 4/H/N/Rect[386.366 345.855 394.126 333.444]/Subtype/Link/Type/Annot>> endobj 2812 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:119. Lykens, J. E., Terrell, C. E., Zoller, E. E., Risma, K. \n& Jordan, M. B. Perf\ orin is a critical physiologic regulator of T- cell activation. Blood 118, 618 626 \(2011\).\r:244)/F 4/H/N/Rect[395.361 345.855 403.121 333.444]/Subtype/Link/Type/Annot>> endobj 2813 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:120. Terrell, C. E. & Jordan, M. B. Perforin deficiency impairs a critical immunor\ egulatory loop involving murine CD8+ Tcells and dendritic cells. Blood 121, 5184 5191 \(2013\).\r:245)/F 4/H/N/Rect[369.763 312.855 377.57 300.444]/Subtype/Link/Type/Annot>> endobj 2814 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:121. Boissonnas, A. etal. Foxp3+ Tcells induce perforin- dependent dendritic c\ ell death in tumor- draining lymph nodes. Immunity 32, 266 278 \(2010\).\r:246)/F 4/H/N/Rect[378.821 312.855 386.628 300.444]/Subtype/Link/Type/Annot>> endobj 2815 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:122. Pfister, D. etal. NASH limits anti- tumour surveillance in immunotherapy- tr\ eated HCC. Nature 592, \n450 456 \(2021\).\r:247)/F 4/H/N/Rect[542.968 279.855 550.658 267.444]/Subtype/Link/Type/Annot>> endobj 2816 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:116. Dudek, M. etal. Auto- aggressive CXCR6+ CD8 Tcells cause liver immune p\ athology in NASH. Nature 592, 444 449 \(2021\).\r:248)/F 4/H/N/Rect[434.769 169.855 442.437 157.444]/Subtype/Link/Type/Annot>> endobj 2817 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:115. Wolf, M. J. etal. Metabolic activation of intrahepatic CD8+ Tcells an\ d NKT cells causes nonalcoholic steatohepatitis and liver cancer via cross- talk with hepatocytes. Cancer Cell 26, 549 564 \(\ 2014\). \nThis study shows the impact :249)/F 4/H/N/Rect[377.138 59.8547 384.787 47.4439]/Subtype/Link/Type/Annot>> endobj 2818 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:123. Syn, W.-K. etal. Accumulation of natural killer Tcells in progressive nonal\ coholic fatty liver disease. Hepatology 51, 1998 2007 \(2010\).\r:250)/F 4/H/N/Rect[385.985 59.8547 393.633 47.4439]/Subtype/Link/Type/Annot>> endobj 2819 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:175. Schwabe, R. F., Tabas, I. & Pajvani, U. B. Mechanisms of fibrosis development\ in nonalcoholic steatohepatitis. Gastroenterology 158, 1913 1928 \(2020\).\r:181)/F 4/H/N/Rect[155.044 639.298 162.243 630.032]/Subtype/Link/Type/Annot>> endobj 2820 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:176. Li, H. etal. Crosstalk between liver \nmacrophages and surrounding cells in \n\ nonalcoholic steatohepatitis. Front. Immunol. \n11, 1169 \(2020\).\r:182)/F 4/H/N/Rect[67.5185 589.298 74.718 580.032]/Subtype/Link/Type/Annot>> endobj 2821 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:177. Browaeys, R., Saelens, W. & Saeys, Y. NicheNet: modeling intercellular commun\ ication by linking ligands to target genes. Nat. Methods 17, 159 162 \(2020\). \nThis study explains the design of a new bio\ informatic tool to probe the intercellu:183)/F 4/H/N/Rect[218.654 569.298 225.854 560.032]/Subtype/Link/Type/Annot>> endobj 2822 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:82. Xiong, X. etal. Landscape of intercellular crosstalk \nin healthy and NASH li\ ver revealed by single- cell secretome gene analysis. Mol. Cell. 75, 644 660.e5 \(2019\). \nThis study shows immune cell div\ ersity and activation in a mouse model :184)/F 4/H/N/Rect[284.753 539.298 289.553 530.032]/Subtype/Link/Type/Annot>> endobj 2823 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:79. Bonnardel, J. etal. Stellate cells, hepatocytes, and endothelial cells impri\ nt the Kupffer cell identity on monocytes colonizing the liver macrophage niche. 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NKT- associated hedgehog and osteopontin drive fibrogenes\ is in non- alcoholic fatty liver disease. Gut 61, 1323 1329 \(2012\).\r:254)/F 4/H/N/Rect[298.911 697.855 306.704 685.444]/Subtype/Link/Type/Annot>> endobj 2832 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:100. Syn, W.-K. etal. Osteopontin is induced by hedgehog pathway activation and \ promotes fibrosis progression in nonalcoholic steatohepatitis. Hepatology 53, \n106 115 \(2011\).\r:255)/F 4/H/N/Rect[209.525 675.855 217.423 663.444]/Subtype/Link/Type/Annot>> endobj 2833 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:115. Wolf, M. J. etal. Metabolic activation of intrahepatic CD8+ Tcells a\ nd NKT cells causes nonalcoholic steatohepatitis and liver cancer via cross- talk with hepatocytes. 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Platelet GPIb is a mediator and potential intervention\ al target for NASH and subsequent liver cancer. Nat. Med. 25, 641 655 \(2019\). \nFujita etal.135 and Malehmir etal\ .136 reveal the potential of anti-:273)/F 4/H/N/Rect[166.228 59.8547 173.871 47.4439]/Subtype/Link/Type/Annot>> endobj 2851 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:137. Jorch, S. K. & Kubes, P. An emerging role for neutrophil extracellular traps \ in noninfectious disease. Nat. Med. 23, 279 287 \(2017\).\r:274)/F 4/H/N/Rect[425.747 686.855 433.448 674.444]/Subtype/Link/Type/Annot>> endobj 2852 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:138. Soehnlein, O., Steffens, S., Hidalgo, A. & Weber, C. Neutrophils as protagoni\ sts and targets in chronic inflammation. Nat. Rev. Immunol. 17, 248 261 \(2017\).\r:275)/F 4/H/N/Rect[434.663 686.855 442.364 674.444]/Subtype/Link/Type/Annot>> endobj 2853 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:139. 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Biophys. 73, 479 487 \(2015\).\r:278)/F 4/H/N/Rect[452.379 653.855 460.125 641.444]/Subtype/Link/Type/Annot>> endobj 2856 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:143. vander Windt, D. J. etal. Neutrophil extracellular traps promote inflammati\ on and development \nof hepatocellular carcinoma in nonalcoholic steatohepatitis. Hepatology 68, 1347 1360 \n\(2018\).\r:279)/F 4/H/N/Rect[462.922 653.855 470.668 641.444]/Subtype/Link/Type/Annot>> endobj 2857 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:141. Zang, S. etal. Neutrophils play a crucial role in the early stage of nonalc\ oholic steatohepatitis via neutrophil elastase in mice. Cell Biochem. Biophys. 73, 479 487 \(2015\).\r:280)/F 4/H/N/Rect[483.419 620.855 490.963 608.444]/Subtype/Link/Type/Annot>> endobj 2858 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:141. Zang, S. etal. Neutrophils play a crucial role in the early stage of nonal\ coholic steatohepatitis via neutrophil elastase in mice. Cell Biochem. Biophys. 73, 479 487 \(2015\).\r:281)/F 4/H/N/Rect[454.912 598.855 463.028 586.444]/Subtype/Link/Type/Annot>> endobj 2859 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:144. Papayannopoulos, V. Neutrophil extracellular traps \nin immunity and disease. \ Nat. Rev. Immunol. 18, 134 147 \(2018\).\r:282)/F 4/H/N/Rect[467.342 587.855 474.825 575.444]/Subtype/Link/Type/Annot>> endobj 2860 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:142. Zhao, X. etal. Neutrophils undergo switch of \napoptosis to NETosis during m\ urine fatty liver injury via S1P receptor 2 signaling. Cell Death Dis. 11, 379 \(2020\).\r:283)/F 4/H/N/Rect[545.049 576.855 552.756 564.444]/Subtype/Link/Type/Annot>> endobj 2861 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:143. vander Windt, D. J. etal. Neutrophil extracellular traps promote inflammat\ ion and development \nof hepatocellular carcinoma in nonalcoholic steatohepatitis. Hepatology 68, 1347 1360 \n\(2018\).\r:284)/F 4/H/N/Rect[377.073 554.855 384.693 542.444]/Subtype/Link/Type/Annot>> endobj 2862 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:142. Zhao, X. etal. Neutrophils undergo switch of \napoptosis to NETosis during \ murine fatty liver injury via S1P receptor 2 signaling. Cell Death Dis. 11, 379 \(2020\).\r:285)/F 4/H/N/Rect[370.594 532.855 378.141 520.444]/Subtype/Link/Type/Annot>> endobj 2863 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:143. vander Windt, D. J. etal. Neutrophil extracellular traps promote inflamma\ tion and development \nof hepatocellular carcinoma in nonalcoholic steatohepatitis. 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Impaired Kupffer cell self- renewal alters the liver response\ to lipid overload during non- alcoholic steatohepatitis. Immunity 53, 627 640.e5 \(2020\). \nThis study shows that monocyte\ - derived Kupffer cells are generated d:289)/F 4/H/N/Rect[528.223 411.855 533.318 399.444]/Subtype/Link/Type/Annot>> endobj 2867 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:81. Remmerie, A. etal. Osteopontin expression identifies a subset of recruite\ d macrophages distinct from Kupffer cells in the fatty liver. Immunity 53, \n641 657.e14 \(2020\). \nThis study highlights ma\ crophage diversity in a mouse model of :290)/F 4/H/N/Rect[534.514 411.855 539.61 399.444]/Subtype/Link/Type/Annot>> endobj 2868 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:146. Seidman, J. S. etal. Niche- specific reprogramming \nof epigenetic landscapes\ drives myeloid cell diversity in nonalcoholic steatohepatitis. Immunity 52, \n1057 1074.e7 \(2020\). \nThis study shows how\ the epigenetic landscape of liver macro:291)/F 4/H/N/Rect[540.806 411.855 548.449 399.444]/Subtype/Link/Type/Annot>> endobj 2869 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:35. Tran, S. etal. Impaired Kupffer cell self- renewal alters the liver respons\ e to lipid overload during non- alcoholic steatohepatitis. Immunity 53, 627 640.e5 \(2020\). \nThis study shows that monocyt\ e- derived Kupffer cells are generated :292)/F 4/H/N/Rect[472.904 367.855 478 355.444]/Subtype/Link/Type/Annot>> endobj 2870 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:81. Remmerie, A. etal. Osteopontin expression identifies a subset of recruit\ ed macrophages distinct from Kupffer cells in the fatty liver. Immunity 53, \n641 657.e14 \(2020\). \nThis study highlights m\ acrophage diversity in a mouse model of:293)/F 4/H/N/Rect[479.197 367.855 484.293 355.444]/Subtype/Link/Type/Annot>> endobj 2871 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:146. Seidman, J. S. etal. Niche- specific reprogramming \nof epigenetic landscape\ s drives myeloid cell diversity in nonalcoholic steatohepatitis. Immunity 52, \n1057 1074.e7 \(2020\). \nThis study shows ho\ w the epigenetic landscape of liver macr:294)/F 4/H/N/Rect[485.489 367.855 493.134 355.444]/Subtype/Link/Type/Annot>> endobj 2872 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:79. Bonnardel, J. etal. Stellate cells, hepatocytes, and endothelial cells impr\ int the Kupffer cell identity on monocytes colonizing the liver macrophage niche. Immunity 51, 638 654.e9 \(2019\). \nThis s\ tudy shows how signals derived from hep:295)/F 4/H/N/Rect[484.264 334.855 489.46 322.444]/Subtype/Link/Type/Annot>> endobj 2873 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:147. Sakai, M. etal. Liver- derived signals sequentially reprogram myeloid enhanc\ ers to initiate and maintain Kupffer cell identity. Immunity 51, 655 670.e8 \(2019\).\r:296)/F 4/H/N/Rect[490.706 334.855 498.498 322.444]/Subtype/Link/Type/Annot>> endobj 2874 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:148. Scott, C. L. etal. Bone marrow- derived monocytes give rise to self- renewin\ g and fully differentiated Kupffer cells. Nat. Commun. 7, 10321 \(2016\).\r:297)/F 4/H/N/Rect[499.744 334.855 507.537 322.444]/Subtype/Link/Type/Annot>> endobj 2875 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:35. Tran, S. etal. 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Tran, S. etal. Impaired Kupffer cell self- renewal alters the liver re\ sponse to lipid overload during non- alcoholic steatohepatitis. Immunity 53, 627 640.e5 \(2020\). \nThis study shows that mo\ nocyte- derived Kupffer cells are gener:307)/F 4/H/N/Rect[310.47 708.855 315.565 696.444]/Subtype/Link/Type/Annot>> endobj 2889 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:Fig. 4 | The diversity of hepatic macrophages during NASH. During non- alcoh\ olic steatohepatitis \(NASH\), embryonically derived Kupffer cells \(KCs\), which are tissue- resident macrophages that inhabit th\ e sinusoids of the healthy liver, are g:308)/F 4/H/N/Rect[333.405 708.855 337.815 696.444]/Subtype/Link/Type/Annot>> endobj 2890 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:149. Krenkel, O. etal. Myeloid cells in liver and bone marrow acquire a functiona\ lly distinct inflammatory phenotype during obesity- related steatohepatitis. Gut 69, 551 563 \(2020\).\r:309)/F 4/H/N/Rect[331.833 609.855 339.761 597.444]/Subtype/Link/Type/Annot>> endobj 2891 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:81. Remmerie, A. etal. Osteopontin expression identifies a subset of recr\ uited macrophages distinct from Kupffer cells in the fatty liver. Immunity 53, \n641 657.e14 \(2020\). \nThis study highlight\ s macrophage diversity in a mouse model:310)/F 4/H/N/Rect[229.391 576.855 234.612 564.444]/Subtype/Link/Type/Annot>> endobj 2892 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:82. Xiong, X. etal. Landscape of intercellular crosstalk \nin healthy and NASH l\ iver revealed by single- cell secretome gene analysis. Mol. Cell. 75, 644 660.e5 \(2019\). \nThis study shows immune cell di\ versity and activation in a mouse model:311)/F 4/H/N/Rect[235.871 576.855 241.092 564.444]/Subtype/Link/Type/Annot>> endobj 2893 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:146. Seidman, J. S. etal. Niche- specific reprogramming \nof epigenetic lands\ capes drives myeloid cell diversity in nonalcoholic steatohepatitis. Immunity 52, \n1057 1074.e7 \(2020\). \nThis study show\ s how the epigenetic landscape of liver :312)/F 4/H/N/Rect[242.351 576.855 250.183 564.444]/Subtype/Link/Type/Annot>> endobj 2894 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:35. Tran, S. etal. Impaired Kupffer cell self- renewal alters the liver r\ esponse to lipid overload during non- alcoholic steatohepatitis. Immunity 53, 627 640.e5 \(2020\). \nThis study shows that m\ onocyte- derived Kupffer cells are gene:313)/F 4/H/N/Rect[286.225 565.855 291.512 553.444]/Subtype/Link/Type/Annot>> endobj 2895 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:150. Jaitin, D. A. etal. Lipid- associated macrophages control metabolic homeosta\ sis in a Trem2-dependent manner. Cell 178, 686 698.e14 \(2019\).\r:314)/F 4/H/N/Rect[163.475 521.855 171.324 509.444]/Subtype/Link/Type/Annot>> endobj 2896 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:81. Remmerie, A. etal. Osteopontin expression identifies a subset of rec\ ruited macrophages distinct from Kupffer cells in the fatty liver. Immunity 53, \n641 657.e14 \(2020\). \nThis study highligh\ ts macrophage diversity in a mouse mode:315)/F 4/H/N/Rect[308.942 466.855 314.221 454.444]/Subtype/Link/Type/Annot>> endobj 2897 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:Fig. 4 | The diversity of hepatic macrophages during NASH. During non- alco\ holic steatohepatitis \(NASH\), embryonically derived Kupffer cells \(KCs\), which are tissue- resident macrophages that inhabit t\ he sinusoids of the healthy liver, are :316)/F 4/H/N/Rect[158.933 444.855 163.42 432.444]/Subtype/Link/Type/Annot>> endobj 2898 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:83. Ramachandran, P. etal. Resolving the fibrotic niche \nof human liver cirrhos\ is at single- cell level. Nature 575, 512 518 \(2019\). \nThis study reveals the immune landscape of human cirrhosis using s\ ingle- cell RNA sequencing.\r:317)/F 4/H/N/Rect[180.725 433.855 185.716 421.444]/Subtype/Link/Type/Annot>> endobj 2899 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:83. Ramachandran, P. etal. Resolving the fibrotic niche \nof human liver cirrho\ sis at single- cell level. Nature 575, 512 518 \(2019\). \nThis study reveals the immune landscape of human cirrhosis using \ single- cell RNA sequencing.\r:318)/F 4/H/N/Rect[300.529 411.855 305.624 399.444]/Subtype/Link/Type/Annot>> endobj 2900 0 obj <>/ExtGState<>/Font<>/ProcSet[/PDF/Text]/Properties<>/Shading<>/XObject<>>> endobj 2901 0 obj <>stream xkG%=GѽTU3ӏ *bb?~w혙HXEF7Pb^7m~sÿ_レ߽߾~%}xj:ܼk;|4o_x܂W//[bݩ)ү_\˓.܄ 74/'igkC\iܓ׹=?\Ycyl_tkC؟brs}tW'[^WO_?/_^=9\oW_^9wKFmuϨsݾ>ֶGت߮Cm|nhEZkoZ5w=pNT0N<8vp׋'hMqwj:S?D[QݳjI5@ӧFе?^?o%mw7nj{k%Ss<=Et,?^ j^G|o 5?hpkO㗓xl-뢃FvJ~]ƸM`5 HfTόJ,?^G,}~\Z<ܾ>~! ,'/1} :5yғNk2|8cNqz+vjh@*]3ļ2L'E'!ae^: 6=ӴdÏ:R'TPU k ';§''?ܬӆ/Fٳ;v# ; H w7?{uw(aꉦt4:6YOaDN^ [ ߛBU(\gTjaOUJTE[=5Oj88 B7`>[[pQ:ڴa0vB2H_fuGuA;V.A6D;wɶ?3[^F/=h-mL}%?g+w E_4wH5LWZ-Jssc|^n:f{9Zhâ0}ď'/<,l~F۱Rg p[O_xActhy #LJܬnL%;۲7?~{x~ v6=|_4ǡ.~Rla,r7`\9/k+~6ÛBw7[̩[3wc4S{ QQ TziM KlwT=fo}->F _v o k0JҺkpW?q9>D{ ijjhXE]}>v;m7'}8?3$E->^J:iو#̈́Ͼ~:ڦD6ty_a} ‚[se=c{w.뻧Zy97!>@GecNc -yg#iv9/xSL0\Q+z`UyuW_3z¯+]C/CIU5' _Rq=p6?swdѿ7Tͮ_?d@:u?2[޵sOA^1:Rsb:G6EṘJ##\_;KսYzᶒ<:㏆+q{x5ø^գy@w"yݚHس'?hk[$4GϷ[ n?DPkIûh:L8>a4mC=LThDO (DKu14O 3~7VYQ xP0)K% j ?FHdԷiŋduV w)¾Xw}/vۛ[75!0/iw~: $ Ƌ oY c@X-|[ Lb^{ӧ/rб,ycbuq֊Ȑvg.bnyK2j7tԴ;=7=v}P=T} Z5@?ľ@!o/H}N0Zۗ<`R"j 4 8h 2du֣?{QPgo!(7`(&6T)[eHԆ_:3VlRE0?*̵i=wDtչ1ҷZflW[n_ؾ])wg&7C6ܙ(9Y@EWϪ}?93wj_?],|go^Ж QMi]Մ);ʺ ΎsɅW3`x;[ aDz.(Q o*;=FX]-⣁X?\0! 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Friedman, S. L., Neuschwander- Tetri, B. A., Rinella, M. & Sanyal, A. J. M\ echanisms of NAFLD development and therapeutic strategies. Nat. Med. 24, 908 922 \(2018\).\r:319)/F 4/H/N/Rect[324.648 719.855 329.852 707.444]/Subtype/Link/Type/Annot>> endobj 3003 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:151. Anstee, Q. M., Reeves, H. L., Kotsiliti, E., Govaere, O. & Heikenwalder, M\ . From NASH to HCC: current concepts and future challenges. Nat. Rev. Gastroenterol. Hepatol. 16, 411 428 \(2019\).\r:320)/F 4/H/N/Rect[332.388 697.855 339.761 685.444]/Subtype/Link/Type/Annot>> endobj 3004 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:115. Wolf, M. J. etal. Metabolic activation of intrahepatic CD8+ Tcells \ and NKT cells causes nonalcoholic steatohepatitis and liver cancer via cross- talk with hepatocytes. Cancer Cell 26, 549 564\ \(2014\). \nThis study shows the impac:321)/F 4/H/N/Rect[322.773 664.855 330.3 652.444]/Subtype/Link/Type/Annot>> endobj 3005 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:92. Shalapour, S. etal. Inflammation- induced IgA+ cells dismantle anti- liv\ er cancer immunity. Nature 551, 340 345 \(2017\). \nThis study shows that IgA is a crucial factor in NASH- induced HCC in mi\ ce.\r:322)/F 4/H/N/Rect[257.857 609.855 263.022 597.444]/Subtype/Link/Type/Annot>> endobj 3006 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:92. Shalapour, S. etal. Inflammation- induced IgA+ cells dismantle anti- li\ ver cancer immunity. Nature 551, 340 345 \(2017\). \nThis study shows that IgA is a crucial factor in NASH- induced HCC in m\ ice.\r:323)/F 4/H/N/Rect[308.738 543.855 314.233 531.444]/Subtype/Link/Type/Annot>> endobj 3007 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:92. Shalapour, S. etal. Inflammation- induced IgA+ cells dismantle anti- l\ iver cancer immunity. Nature 551, 340 345 \(2017\). \nThis study shows that IgA is a crucial factor in NASH- induced HCC in \ mice.\r:324)/F 4/H/N/Rect[232.663 499.855 237.906 487.444]/Subtype/Link/Type/Annot>> endobj 3008 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:152. St Paul, M. & Ohashi, P. S. The roles of CD8+ Tcell subsets in antitumor i\ mmunity. Trends Cell Biol. 30, 695 704 \(2020\).\r:325)/F 4/H/N/Rect[289.679 444.855 297.209 432.444]/Subtype/Link/Type/Annot>> endobj 3009 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:153. Ma, C. etal. NAFLD causes selective CD4+ T lymphocyte loss and promotes he\ patocarcinogenesis. Nature 531, 253 257 \(2016\).\r:326)/F 4/H/N/Rect[332.023 422.855 339.761 410.444]/Subtype/Link/Type/Annot>> endobj 3010 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:153. Ma, C. etal. NAFLD causes selective CD4+ T lymphocyte loss and promotes h\ epatocarcinogenesis. Nature 531, 253 257 \(2016\).\r:327)/F 4/H/N/Rect[168.417 378.855 176.014 366.444]/Subtype/Link/Type/Annot>> endobj 3011 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:110. Gomes, A. L. etal. Metabolic inflammation- associated IL-17A causes non- \ alcoholic steatohepatitis and hepatocellular carcinoma. Cancer Cell 30, 161 175 \(2016\).\r:328)/F 4/H/N/Rect[304.542 301.855 312.466 289.444]/Subtype/Link/Type/Annot>> endobj 3012 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:143. vander Windt, D. J. etal. Neutrophil extracellular traps promote inflamm\ ation and development \nof hepatocellular carcinoma in nonalcoholic steatohepatitis. Hepatology 68, 1347 1360 \n\(2018\).\r:3\ 29)/F 4/H/N/Rect[331.981 169.855 339.761 157.444]/Subtype/Link/Type/Annot>> endobj 3013 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:143. vander Windt, D. J. etal. 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Science 367, 652 660 \(2020\). \nThis study shows the crucial role of the \nAMPK caspase 6 axis in NASH p\ athogenesis.\r:342)/F 4/H/N/Rect[419.45 224.855 424.546 212.444]/Subtype/Link/Type/Annot>> endobj 3026 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:162. Kruger, A. J. etal. Prolonged cenicriviroc therapy reduces hepatic fibrosis \ despite steatohepatitis \nin a diet- induced mouse model of nonalcoholic steatohepatitis. Hepatol. Commun. 2, 529 545 \(2018\)\ .\r:343)/F 4/H/N/Rect[371.176 158.855 378.977 146.444]/Subtype/Link/Type/Annot>> endobj 3027 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:163. Lefebvre, E. etal. Antifibrotic effects of the dual \nCCR2/CCR5 antagonist ce\ nicriviroc in animal models of liver and kidney fibrosis. PLoS One 11, e0158156 \(2016\).\r:344)/F 4/H/N/Rect[380.226 158.855 388.027 146.444]/Subtype/Link/Type/Annot>> endobj 3028 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:11. 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Invest. 115, 209 2\ 18 \(2005\).\r:346)/F 4/H/N/Rect[542.744 59.8547 550.658 47.4439]/Subtype/Link/Type/Annot>> endobj 3030 0 obj <>/ExtGState<>/Font<>/ProcSet[/PDF/Text]/XObject<>>> endobj 3031 0 obj <>stream x}Iˏ?";xԽnόUXc0(U$ s[m8q;Dfؖ̌˹~ 7ӧT=|.Uݽqu|*q׷ex]2uwfHJݭ_Z}}-N13+EuYWjlTU%4{هߨf=~N:-?~Љ^,;H!× A!)Em/T/}Jl|^pUZwdmh/ɼZmɼv}cRQU2o|+V\֛d.2Z/Iom_zf{ԃz.N-B-,7ÿ3-&\ss3{_T.k6E]6MWzފEuUyeyrU%L-"mgYfKFO"L£2}~Po4ȵ{nߵ5a6 La͔ٔ/ן;JXTU%(iBp.ꊬvˠR@ N^¸tk~la0Zrګ=y_6n&9"-kB̅ JSi96%l硝bGۍ:g{找2I_V52YK=Kw&=6XPF1n&qcoP%;]j<#OT> icsPǤ"\f&Rw_ņ$'k֨͌V3z.a)t ]RZ7yUu U*@ ֮xpRhn7\at7P0dΈ,+X0~d } e_(Voo6˞6g0gN q״^>vpT'QEQk= QXKr|FYlLSZ)Rd xؕ opS6z@][yuYn [*D{l`Z5iKI7.UG yVxA:Sl zyj;olQNtwRZӚc5^b(}^f+vBU4n\6m$Fw'o1*V;2q`vTG4B*2w:/`f'pk"fvG|yg6Du 46)EݤYZ:*em3'cӌT4{O4tن6g\u&zJ]:T]k#l~E|3 md6lWW"ōl]>hnr]ڨ-JWd,s+;B5c7ۖ7 ??^i2_G_}'&^3*=00,~ {ݜit+O&\AP]`wURϭƗQT"maY\>h\BBGCq]1O[;o&ŗ_M3 z_v& lH*Z>A#4[[]oe67[+NqGq\F4+oɧ~2o `$,v4Ph*ޮg˵xFPVb @B {@.&D$v} ^G*eRaV_]Ao-x7܌vθQ@!\ myd}:^4FWX٠`,Z_gnui_d݈?e\MTfZ*ֻwv\kMPhւؿha!uXkx4d$2v[mXhv$p>&!.!LiaDԷS]/ű\ց<}dmnZ@G(a,]>D^> uj?XW]<UU+u7dgaffc4 IӍ7uo+=fkhaԊx+-B*ŻQ>tIL Q0&Vᾧr[->i:CP/Aڅfx~`j61z\9m?{$u1#Əֿ -Ite]W֣[c.)5 XMݨgiXDȅ}ްh ^QdDř`,6F& @Ʌ!  ޴:jA#GDŽbTFrϬrmy]Ʀ%|tR^f,&Q<1騾cO׃anUZ$3Ln\kJ :wCЕNo2eZ I>pVb QccC-J0Kir̎Pe 7oQQ{8X ߇[5:sR ?&l×8p^$`nz\tb|r:|;hNЬl`;lՁfzՏƈcx!|c >  ~4D9\3طܜPp3KѴ2]';7@vFA'g~+|qL?ӘRTofLu˃u|x=?{X׋:P4_VUk# xdL&]-Ie&)`z^?;!A m.%":$` 0 '^ao!Kr;̃Lc1;PS϶m>/_Rf6pxĄ|gn)֖W#žg?XȂ(2MG>Bӆ Fi@H0lN-:b9 &C>)ňĽ|lc72ޢ}nЅ I "*q #aZib +`Oa+ϼb䀎;~vXyKz`C5>=bYdf+zO3̓v}ڂx1sL 11sL*q%9K ]G=3˂#}"ӕe؊z߇"8:o_% I%G4j@( %߶$bPu V?]ʬ3~v4Ni_U2M VQE8*6Ifp"Qa| R]Ϝl8Q00G`LPﱍB檐;pef&WY]0#dž K ɫA]M)K 'FdY~B $^= MXzg^%pWW<,8]⋹_br4sßE7Hؒv $dUf2ڧ\FCl$bjBp5HLlҋ 'T{EЩm+-*"!bJZcW_1ZTlY̸#'jȆn[-)j5 }'%uM|d]S(f 87.!T4I9 baz&U"Ob|wcT$2,;rM$™ʔ8\/Sz\֭ΔƫxJӿ$:ֶccNpSz02l$HHnVkw8 ̤I[=&Kb^I%bxKwJ +M~`ݤBSQg)NBFgL`Y33ںNB9?T;?ch/+:()cI^9ajj51  >0+~J۳.v *=(Fcֳ`}#'E -C,}.P(q=XxWkM[qbƹ﵀GXsk;\RR&l+J)F{F0PKQc_,;IKé$nOI6sD$E'H*"BuL0ٱ6ўB xc Ff0 '!Y^%$4wqq 1#= Z1GThU%`l"8ALP[2AlZRBa0eE ~P jckìܶ,X ,+gp-џQ '8\)Bx%u@/ lΜ@|͜u" ~ҋ2frϲm5Dz!^Ş+uLsRO,yBarhឧ+HИXY:@2֬2r+qNͱ' ,Qn5l=ǖ3~rEMYqcΉ{ޜOJ=㯧fu:X >ՁWR Nh(FRq>5ҨEsOW>3%a*R6Nb %hx:8/8>!8G #G2&wVF . 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Senolytic CAR Tcells reverse senescence- associated patholo\ gies. Nature 583, 127 132 \(2020\). \nOne of the first studies showing that CAR Tcells could be used to combat fibrosis in \ the context \nof NASH.\r:350)/F 4/H/N/Rect[219.5 521.855 227.143 509.444]/Subtype/Link/Type/Annot>> endobj 3038 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:165. Amor, C. etal. Senolytic CAR Tcells reverse senescence- associated pathol\ ogies. Nature 583, 127 132 \(2020\). \nOne of the first studies showing that CAR Tcells could be used to combat fibrosis in\ the context \nof NASH.\r:351)/F 4/H/N/Rect[331.928 499.855 339.761 487.444]/Subtype/Link/Type/Annot>> endobj 3039 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:167. Thomas, J. A. etal. Macrophage therapy for murine liver fibrosis recruits ho\ st effector cells improving fibrosis, regeneration, and function. Hepatology 53, 2003 2015 \(2011\).\r:352)/F 4/H/N/Rect[288.622 477.855 296.265 465.444]/Subtype/Link/Type/Annot>> endobj 3040 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:168. Moroni, F. etal. Safety profile of autologous macrophage therapy for liver c\ irrhosis. Nat. 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SVhuQw9eLދaXvCؠp5N(t:AM況Ũһg#fUaǡ D')aJd҂H))Y3e٤iv71fb㎆&CZtubPj{W6ylt~ Xw[s4^ AAAAA _ 9LSus endstream endobj 3496 0 obj <> endobj 3497 0 obj <> endobj 3498 0 obj <> endobj 3499 0 obj <> endobj 3500 0 obj <> endobj 3501 0 obj <> endobj 3502 0 obj <> endobj 3503 0 obj <> endobj 3504 0 obj <> endobj 3505 0 obj <> endobj 3506 0 obj <> endobj 3507 0 obj <> endobj 3508 0 obj <> endobj 3509 0 obj <> endobj 3510 0 obj <<>> endobj 3511 0 obj <>stream application/pdf doi:10.1038/s41577-021-00639-3 Springer US Nature Reviews Immunology, doi:10.1038/s41577-021-00639-3 Immune cell-mediated features of non-alcoholic steatohepatitis Thierry Huby Emmanuel L. 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Sun, X. etal. Neutralization of oxidized phospholipids ameliorates non- alcoh\ olic steatohepatitis. Cell Metab. 31, 189 206.e8 \(2020\). \nThis study shows the beneficial effect of neutralizing oxidized\ phospholipids on NASH progression.\r:114)/F 4/H/N/Rect[165.4 675.855 170.495 663.444]/Subtype/Link/Type/Annot>> endobj 1588 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:Fig. 1 | Contributing factors in NAFLD progression and NASH pathogenesis. N\ on- alcoholic fatty liver disease \(NAFLD\) is a progressive disease that starts with simple steatosis \(non- alcoholic fatty liv\ er \(NAFL\)\) and can evolve to a more com:115)/F 4/H/N/Rect[290.624 631.855 294.997 619.444]/Subtype/Link/Type/Annot>> endobj 1589 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:50. Ganz, M. etal. Progression of non- alcoholic steatosis to steatohepatitis and\ fibrosis parallels cumulative accumulation of danger signals that promote inflammation and liver tumors in a high fat- choleste\ rol-sugar diet model in mice. J. Tra:116)/F 4/H/N/Rect[435.887 730.855 440.908 718.444]/Subtype/Link/Type/Annot>> endobj 1590 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:51. Kakazu, E., Mauer, A. S., Yin, M. & Malhi, H. Hepatocytes release ceramide- en\ riched pro- inflammatory extracellular vesicles in an IRE1\n- dependent manner. J. Lipid Res. 57, 233 245 \(2016\).\r:117)/F 4/H/N/Rect[524.315 730.855 529.336 718.444]/Subtype/Link/Type/Annot>> endobj 1591 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:52. Dasgupta, D. etal. IRE1A stimulates hepatocyte- derived extracellular vesicle\ s that promote inflammation in mice with steatohepatitis. 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These \nlobules consist of hepatocytes organized around a central vein tha\ t is connected to the hepatic artery a:159)/F 4/H/N/Rect[544.594 125.855 548.858 113.444]/Subtype/Link/Type/Annot>> endobj 1615 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:70. Fernandez- Ruiz, D. etal. Liver- resident memory \nCD8+ Tcells form a fron\ t- line defense against \nmalaria liver- stage infection. Immunity 45, 889 902 \(2016\).\r:160)/F 4/H/N/Rect[545.53 114.855 550.658 102.444]/Subtype/Link/Type/Annot>> endobj 1616 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:72. MacParland, S. A. etal. Single cell RNA sequencing of human liver reveals dis\ tinct intrahepatic macrophage populations. Nat. Commun. 9, 4383 \(2018\).\r:161)/F 4/H/N/Rect[436.766 92.8547 441.819 80.4439]/Subtype/Link/Type/Annot>> endobj 1617 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:73. Moro- Sibilot, L. etal. 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Immunity 53, \n641 657.e14 \(2020\). \nThis study highlights macro\ phage diversity in a mouse model of NAS:127)/F 4/H/N/Rect[321.515 383.021 326.315 373.755]/Subtype/Link/Type/Annot>> endobj 1627 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:151. Anstee, Q. M., Reeves, H. L., Kotsiliti, E., Govaere, O. & Heikenwalder, M. \ From NASH to HCC: current concepts and future challenges. Nat. Rev. Gastroenterol. Hepatol. 16, 411 428 \(2019\).\r:128)/F 4/H/N/Rect[327.319 383.021 334.518 373.755]/Subtype/Link/Type/Annot>> endobj 1628 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:171. Im, Y. R. etal. A systematic review of animal models \nof NAFLD finds high- f\ at, high- fructose diets most closely resemble human NAFLD. Hepatology 74, 1884 1901 \(2021\).\r:129)/F 4/H/N/Rect[301.046 333.021 308.246 323.755]/Subtype/Link/Type/Annot>> endobj 1629 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:172. Asgharpour, A. etal. 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Anstee, Q. M., Reeves, H. L., Kotsiliti, E., Govaere, O. & Heikenwalder, M.\ From NASH to HCC: current concepts and future challenges. Nat. Rev. Gastroenterol. Hepatol. 16, 411 428 \(2019\).\r:133)/F 4/H/N/Rect[217.883 183.021 225.082 173.755]/Subtype/Link/Type/Annot>> endobj 1633 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:173. Hansen, H. H. etal. Mouse models of nonalcoholic steatohepatitis in preclini\ cal drug development. \nDrug Discov. Today 22, 1707 1718 \(2017\).\r:134)/F 4/H/N/Rect[226.086 183.021 233.286 173.755]/Subtype/Link/Type/Annot>> endobj 1634 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:174. Machado, M. V. etal. Mouse models of diet- induced nonalcoholic steatohepati\ tis reproduce the heterogeneity of the human disease. PLoS One 10, e0127991 \(2015\).\r:135)/F 4/H/N/Rect[317.207 153.021 324.407 143.755]/Subtype/Link/Type/Annot>> endobj 1635 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:115. 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YN>&^]c`k$Ɖy$[H8)ɳh%:4!qY&vrTq*ok0@x]xcɅabp&טmp}HɆ)D2Wml:هA E_~flY1GWэ)|n=bWm쫸ބ6Wo"p\Wv i_^? ( endstream endobj 1647 0 obj <> endobj 1648 0 obj [1649 0 R 1650 0 R 1651 0 R 1652 0 R 1653 0 R 1654 0 R 1655 0 R 1656 0 R 1657 0 R 1658 0 R 1659 0 R 1660 0 R] endobj 1649 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:74. David, B. A. etal. Combination of mass cytometry \nand imaging analysis reveal\ s origin, location, and functional repopulation of liver myeloid cells in mice. Gastroenterology 151, 1176 1191 \(2016\).\r:\ 164)/F 4/H/N/Rect[162.275 202.855 167.505 190.444]/Subtype/Link/Type/Annot>> endobj 1650 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:74. David, B. A. etal. Combination of mass cytometry \nand imaging analysis revea\ ls origin, location, and functional repopulation of liver myeloid cells in mice. Gastroenterology 151, 1176 1191 \(2016\).\r\ :165)/F 4/H/N/Rect[187.48 169.855 192.788 157.444]/Subtype/Link/Type/Annot>> endobj 1651 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:75. Sierro, F. etal. A liver capsular network of monocyte- derived macrophages re\ stricts hepatic dissemination of intraperitoneal bacteria by neutrophil recruitment. Immunity 47, 374 388.e6 \(2017\).\r:166)/F 4/H/N/Rect[193.466 125.855 198.901 113.444]/Subtype/Link/Type/Annot>> endobj 1652 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:Fig. 2 | Immune landscape of the healthy liver. The liver is composed \no\ f lobules that are repeated hexagonal anatomical units. These \nlobules consist of hepatocytes organized around a central vein t\ hat is connected to the hepatic artery:167)/F 4/H/N/Rect[220.142 125.855 224.823 113.444]/Subtype/Link/Type/Annot>> endobj 1653 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:75. Sierro, F. etal. A liver capsular network of monocyte- derived macrophages r\ estricts hepatic dissemination of intraperitoneal bacteria by neutrophil recruitment. Immunity 47, 374 388.e6 \(2017\).\r:16\ 8)/F 4/H/N/Rect[295.452 103.855 300.827 91.4439]/Subtype/Link/Type/Annot>> endobj 1654 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:76. Gomez Perdiguero, E. etal. Tissue- resident macrophages originate from yolk- \ sac-derived \nerythro- myeloid progenitors. Nature 518, 547 551 \(2015\).\r:169)/F 4/H/N/Rect[326.772 59.8547 331.882 47.4439]/Subtype/Link/Type/Annot>> endobj 1655 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:78. Liu, Z. etal. Fate mapping via Ms4a3-expression history traces monocyte- deri\ ved cells. Cell 178, 1509 1525.e19 \(2019\).\r:170)/F 4/H/N/Rect[334.651 59.8547 339.761 47.4439]/Subtype/Link/Type/Annot>> endobj 1656 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:Fig. 2 | Immune landscape of the healthy liver. The liver is composed \n\ of lobules that are repeated hexagonal anatomical units. These \nlobules consist of hepatocytes organized around a central vein \ that is connected to the hepatic arter:171)/F 4/H/N/Rect[543.867 246.855 548.494 234.444]/Subtype/Link/Type/Annot>> endobj 1657 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:79. Bonnardel, J. etal. Stellate cells, hepatocytes, and endothelial cells imprin\ t the Kupffer cell identity on monocytes colonizing the liver macrophage niche. Immunity 51, 638 654.e9 \(2019\). \nThis stu\ dy shows how signals derived from hepat:172)/F 4/H/N/Rect[495.739 202.855 501.156 190.444]/Subtype/Link/Type/Annot>> endobj 1658 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:80. Gola, A. etal. Commensal- driven immune zonation \nof the liver promotes host \ defence. Nature 589, \n131 136 \(2021\).\r:173)/F 4/H/N/Rect[395.203 158.855 400.298 146.444]/Subtype/Link/Type/Annot>> endobj 1659 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:81. Remmerie, A. etal. Osteopontin expression identifies a subset of recruited \ macrophages distinct from Kupffer cells in the fatty liver. Immunity 53, \n641 657.e14 \(2020\). \nThis study highlights macr\ ophage diversity in a mouse model of NA:174)/F 4/H/N/Rect[527.321 59.8547 532.416 47.4439]/Subtype/Link/Type/Annot>> endobj 1660 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevImmun_639.indd:82. Xiong, X. etal. Landscape of intercellular crosstalk \nin healthy and NASH liv\ er revealed by single- cell secretome gene analysis. Mol. 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