Immunopathogenesis of non-alcoholic fatty liver disease

点击翻译按钮获取中文摘要

SUMMARY The unabated obesity pandemic drives dramatic increases in the incidence of common metabolic derangements including non-alchoholic fatty liver disease (NAFLD). The immune system provides a critical causative link between obesity and NAFLD pathogenesis. Activation of the interleukin (IL) 17 axis is a key contributor to NAFLD progression. Given the therapeutic promise for targeting pathogenic immune responses in NAFLD, enhanced understanding of the cellular and molecular mechanisms underlying IL-17 axis-dependent pathogenicity is a high priority. In NAFLD, Th17 cells are the primary hepatic producers of IL-17A. Although Th17 cell heterogeneity is a known determinant of inflammatory disease severity, exclusive cellular characteristics and function of hepatic Th17 cells in NAFLD have not been studied. Here, we demonstrate that NAFLD progression correlates with accrual of a unique inflammatory hepatic Th17 cell subset (ihTh17) that exhibits metabolic, epigenetic, and transcriptional signatures distinct from the conventional hepatic Th17 cells (chTh17) and from the inflammatory Th17 cells observed in mouse models of EAE and Crohn’s disease. Our exciting preliminary data, in mice, further suggest that: (i) obesity-associated microbiome regulates ihTh17 cell activation; (ii) the CXCR3 axis regulates ihTh17-induced NAFLD pathogenesis; and (iii) ihTh17 cells are sufficient to exacerbate NAFLD progression above the level induced by chTh17 cells. Importantly, these findings are recapitulated in human disease where NASH patients exhibit increased CXCR3 axis activation and hepatic infiltration of ihTh17 cells. Together, our findings and existing literature strongly support the central hypothesis that obesity-driven hepatic accrual of ihTh17 cells is critical to the pathogenesis of NAFLD. Our overaching hypothesis will be tested via intently designed aims that will: (1) Determine the factors contributing to ihTh17 emergence in NAFLD; (2) Determine the contribution of the CXCR3 axis to ihTh17 hepatic accrual in NAFLD; and (3) Determine the contribution of cellular metabolism to ihTh17 inflammatory vigor and NAFLD pathogenesis. Mechanistic hypotheses associated with these aims, respectively, are: (a) the obesity-associated inflammatory and microbiome environment shape the emergence of ihTh17 cell phenotype; (b) CXCR3 expression by ihTh17 cells and CXCL10 expression by hepatocytes promotes ihTh17 hepatic accrual; and (c) PKM2-driven glycolysis fuels ihTh17 cytokine production and exacerbates NAFLD pathogenesis. Thus, our proposed studies will provide new knowledge into previously unexplored cellular and molecular processes licensing ihTh17 pathogenic potential in experimental NAFLD and the extent of their involvement in human disease. As therapies to NAFLD are lacking, new insights to IL-17 axis- dependent pathogenic mechanisms hold potential for discovery of novel predictive, preventive and therapeutic avenues.