TY - JOUR
T1 - PKM2-dependent metabolic skewing of hepatic Th17 cells regulates pathogenesis of non-alcoholic fatty liver disease
AU - Moreno-Fernandez, Maria E.
AU - Giles, Daniel A.
AU - Oates, Jarren R.
AU - Chan, Calvin C.
AU - Damen, Michelle S.M.A.
AU - Doll, Jessica R.
AU - Stankiewicz, Traci E.
AU - Chen, Xiaoting
AU - Chetal, Kashish
AU - Karns, Rebekah
AU - Weirauch, Matthew T.
AU - Romick-Rosendale, Lindsey
AU - Xanthakos, Stavra A.
AU - Sheridan, Rachel
AU - Szabo, Sara
AU - Shah, Amy S.
AU - Helmrath, Michael A.
AU - Inge, Thomas H.
AU - Deshmukh, Hitesh
AU - Salomonis, Nathan
AU - Divanovic, Senad
N1 - Funding Information:
This work was supported in part by National Institutes of Health (NIH) R01DK099222 and American Diabetes Association (ADA) 1-18-IBS-100 (to S.D.), CCHMC Pediatric Diabetes and Obesity Center (to S.D., M.A.H., and T.H.I.), Department of Defense (DoD) W81XWH2010392 (to S.D. and M.A.H.), R01DK099222-02S1 (associated with S.D., M.E.M.-F., and J.R.O.), American Heart Association (AHA) 17POST33650045 and ADA 1-19-PMF-019 (to M.E.M.-F.), CCRF Endowed Scholar Award (to S.D. and M.T.W.), NIH T32AI118697 (associated with D.A.G. and C.C.C.), NIH T32GM063483-14 (associated with C.C.C.), NIH R01HL142708-01 (to H.D.), University of Cincinnati Provost Graduate Fellowship (to J.R.O.), The Arnold W. Strauss Fellow Award (to J.R.D.), and NIH P30 DK078392 of the Digestive Disease Research Core Center at CCHMC (associated with S.D.). We thank S. Waggoner for providing CXCR3-deficient mice, C. Pasare for providing TNFα-deficient mice, and M. Jordan for providing IFNγ-deficient mice.
Funding Information:
This work was supported in part by National Institutes of Health (NIH) R01DK099222 and American Diabetes Association (ADA) 1-18-IBS-100 (to S.D.), CCHMC Pediatric Diabetes and Obesity Center (to S.D. M.A.H. and T.H.I.), Department of Defense (DoD) W81XWH2010392 (to S.D. and M.A.H.), R01DK099222-02S1 (associated with S.D. M.E.M.-F. and J.R.O.), American Heart Association (AHA) 17POST33650045 and ADA 1-19-PMF-019 (to M.E.M.-F.), CCRF Endowed Scholar Award (to S.D. and M.T.W.), NIH T32AI118697 (associated with D.A.G. and C.C.C.), NIH T32GM063483-14 (associated with C.C.C.), NIH R01HL142708-01 (to H.D.), University of Cincinnati Provost Graduate Fellowship (to J.R.O.), The Arnold W. Strauss Fellow Award (to J.R.D.), and NIH P30 DK078392 of the Digestive Disease Research Core Center at CCHMC (associated with S.D.). We thank S. Waggoner for providing CXCR3-deficient mice, C. Pasare for providing TNF?-deficient mice, and M. Jordan for providing IFN?-deficient mice. M.E.M.-F. D.A.G. J.R.O. C.C.C. M.S.M.A.D. J.R.D. T.E.S. R.K. M.T.W. L.R.-R. R.S. S.S. H.D. N.S. and S.D. participated in data generation. M.E.M.-F. R.K. L.R.-R. S.A.X. R.S. S.S. A.S.S. H.D. N.S. X.C. K.C. M.T.W. and S.D. participated in analysis and interpretation of data. M.A.H. and T.H.I. provided materials, technical support, and interpretation of data and participated in review of the manuscript. M.E.M.-F. and S.D. participated in the conception and design of the study and wrote the manuscript. All authors have reviewed the manuscript and approve the final version. S.D. is a consultant for Janssen Research & Development.
Publisher Copyright:
© 2021 Elsevier Inc.
PY - 2021/6/1
Y1 - 2021/6/1
N2 - Emerging evidence suggests a key contribution to non-alcoholic fatty liver disease (NAFLD) pathogenesis by Th17 cells. The pathogenic characteristics and mechanisms of hepatic Th17 cells, however, remain unknown. Here, we uncover and characterize a distinct population of inflammatory hepatic CXCR3+Th17 (ihTh17) cells sufficient to exacerbate NAFLD pathogenesis. Hepatic ihTh17 cell accrual was dependent on the liver microenvironment and CXCR3 axis activation. Mechanistically, the pathogenic potential of ihTh17 cells correlated with increased chromatin accessibility, glycolytic output, and concomitant production of IL-17A, IFNγ, and TNFα. Modulation of glycolysis using 2-DG or cell-specific PKM2 deletion was sufficient to reverse ihTh17-centric inflammatory vigor and NAFLD severity. Importantly, ihTh17 cell characteristics, CXCR3 axis activation, and hepatic expression of glycolytic genes were conserved in human NAFLD. Together, our data show that the steatotic liver microenvironment regulates Th17 cell accrual, metabolism, and competence toward an ihTh17 fate. Modulation of these pathways holds potential for development of novel therapeutic strategies for NAFLD.
AB - Emerging evidence suggests a key contribution to non-alcoholic fatty liver disease (NAFLD) pathogenesis by Th17 cells. The pathogenic characteristics and mechanisms of hepatic Th17 cells, however, remain unknown. Here, we uncover and characterize a distinct population of inflammatory hepatic CXCR3+Th17 (ihTh17) cells sufficient to exacerbate NAFLD pathogenesis. Hepatic ihTh17 cell accrual was dependent on the liver microenvironment and CXCR3 axis activation. Mechanistically, the pathogenic potential of ihTh17 cells correlated with increased chromatin accessibility, glycolytic output, and concomitant production of IL-17A, IFNγ, and TNFα. Modulation of glycolysis using 2-DG or cell-specific PKM2 deletion was sufficient to reverse ihTh17-centric inflammatory vigor and NAFLD severity. Importantly, ihTh17 cell characteristics, CXCR3 axis activation, and hepatic expression of glycolytic genes were conserved in human NAFLD. Together, our data show that the steatotic liver microenvironment regulates Th17 cell accrual, metabolism, and competence toward an ihTh17 fate. Modulation of these pathways holds potential for development of novel therapeutic strategies for NAFLD.
KW - CXCR3
KW - IFNγ
KW - NAFLD
KW - PKM
KW - T cell
KW - TNF
KW - cellular metabolism
KW - glycolysis
KW - liver
KW - obesity
UR - http://www.scopus.com/inward/record.url?scp=85106627889&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85106627889&partnerID=8YFLogxK
U2 - 10.1016/j.cmet.2021.04.018
DO - 10.1016/j.cmet.2021.04.018
M3 - Article
C2 - 34004162
AN - SCOPUS:85106627889
SN - 1550-4131
VL - 33
SP - 1187-1204.e9
JO - Cell Metabolism
JF - Cell Metabolism
IS - 6
ER -
