PKM2-dependent metabolic skewing of hepatic Th17 cells regulates pathogenesis of non-alcoholic fatty liver disease

Maria E. Moreno-Fernandez; Daniel A. Giles; Jarren R. Oates; Calvin C. Chan; Michelle S.M.A. Damen; Jessica R. Doll; Traci E. Stankiewicz; Xiaoting Chen; Kashish Chetal; Rebekah Karns; Matthew T. Weirauch; Lindsey Romick-Rosendale; Stavra A. Xanthakos; Rachel Sheridan; Sara Szabo; Amy S. Shah; Michael A. Helmrath; Thomas H. Inge; Hitesh Deshmukh; Nathan Salomonis; Senad Divanovic

doi:10.1016/j.cmet.2021.04.018

PKM2-dependent metabolic skewing of hepatic Th17 cells regulates pathogenesis of non-alcoholic fatty liver disease

Maria E. Moreno-Fernandez, Daniel A. Giles, Jarren R. Oates, Calvin C. Chan, Michelle S.M.A. Damen, Jessica R. Doll, Traci E. Stankiewicz, Xiaoting Chen, Kashish Chetal, Rebekah Karns, Matthew T. Weirauch, Lindsey Romick-Rosendale, Stavra A. Xanthakos, Rachel Sheridan, Sara Szabo, Amy S. Shah, Michael A. Helmrath, Thomas H. Inge, Hitesh Deshmukh, Nathan SalomonisSenad Divanovic^*

^*Corresponding author for this work

Surgery

Research output: Contribution to journal › Article › peer-review

72 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	1187-1204.e9
Journal	Cell Metabolism
Volume	33
Issue number	6
DOIs	https://doi.org/10.1016/j.cmet.2021.04.018
State	Published - Jun 1 2021

Funding

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. 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.

Keywords

CXCR3
IFNγ
NAFLD
PKM
T cell
TNF
cellular metabolism
glycolysis
liver
obesity

ASJC Scopus subject areas

Molecular Biology
Physiology
Cell Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.cmet.2021.04.018

Cite this

Moreno-Fernandez, M. E., Giles, D. A., Oates, J. R., Chan, C. C., Damen, M. S. M. A., Doll, J. R., Stankiewicz, T. E., Chen, X., Chetal, K., Karns, R., Weirauch, M. T., Romick-Rosendale, L., Xanthakos, S. A., Sheridan, R., Szabo, S., Shah, A. S., Helmrath, M. A., Inge, T. H., Deshmukh, H., ... Divanovic, S. (2021). PKM2-dependent metabolic skewing of hepatic Th17 cells regulates pathogenesis of non-alcoholic fatty liver disease. Cell Metabolism, 33(6), 1187-1204.e9. https://doi.org/10.1016/j.cmet.2021.04.018

@article{81417aca074546b490683f125ee5b23b,

title = "PKM2-dependent metabolic skewing of hepatic Th17 cells regulates pathogenesis of non-alcoholic fatty liver disease",

abstract = "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.",

keywords = "CXCR3, IFNγ, NAFLD, PKM, T cell, TNF, cellular metabolism, glycolysis, liver, obesity",

author = "Moreno-Fernandez, {Maria E.} and Giles, {Daniel A.} and Oates, {Jarren R.} and Chan, {Calvin C.} and Damen, {Michelle S.M.A.} and Doll, {Jessica R.} and Stankiewicz, {Traci E.} and Xiaoting Chen and Kashish Chetal and Rebekah Karns and Weirauch, {Matthew T.} and Lindsey Romick-Rosendale and Xanthakos, {Stavra A.} and Rachel Sheridan and Sara Szabo and Shah, {Amy S.} and Helmrath, {Michael A.} and Inge, {Thomas H.} and Hitesh Deshmukh and Nathan Salomonis and Senad Divanovic",

note = "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: {\textcopyright} 2021 Elsevier Inc.",

year = "2021",

month = jun,

day = "1",

doi = "10.1016/j.cmet.2021.04.018",

language = "English (US)",

volume = "33",

pages = "1187--1204.e9",

journal = "Cell Metabolism",

issn = "1550-4131",

publisher = "Cell Press",

number = "6",

}

Moreno-Fernandez, ME, Giles, DA, Oates, JR, Chan, CC, Damen, MSMA, Doll, JR, Stankiewicz, TE, Chen, X, Chetal, K, Karns, R, Weirauch, MT, Romick-Rosendale, L, Xanthakos, SA, Sheridan, R, Szabo, S, Shah, AS, Helmrath, MA, Inge, TH, Deshmukh, H, Salomonis, N & Divanovic, S 2021, 'PKM2-dependent metabolic skewing of hepatic Th17 cells regulates pathogenesis of non-alcoholic fatty liver disease', Cell Metabolism, vol. 33, no. 6, pp. 1187-1204.e9. https://doi.org/10.1016/j.cmet.2021.04.018

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

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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 -

PKM2-dependent metabolic skewing of hepatic Th17 cells regulates pathogenesis of non-alcoholic fatty liver disease

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UN SDGs

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