Lipid antigens as metabolic regulators of inflammation in non-alcoholic fatty liver disease
Final Report Abstract
Cluster of differentiation 1d (CD1d) is an atypical antigen-presenting glycoprotein that binds diverse lipid classes. CD1d broadly surveys the cell for endogenous (self) and exogenous (e.g. microbial) lipids and presents those lipids to a subset of T cells, named natural killer T (NKT) cells. NKT cells exhibit rapid and abundant cytokine secretion upon antigen recognition, leading to a broad activation of other innate and adaptive immune cell populations such as dendritic cells, natural killer cells, B cells, and conventional T cells. NKT cells have been linked to the progression of non-alcoholic fatty liver disease (NAFLD), a prevalent metabolic liver disease which is associated with immune-mediated progression to liver fibrosis and cirrhosis. Moreover, work by others had shown that CD1d-restricted activation of NKT cells by hepatocytes is modulated by exposure to dietary fatty acids, suggesting a critical role of cellular lipid metabolism in the regulation of CD1d-restricted antigen presentation by hepatocytes. Based on these findings we aimed to investigate whether metabolic alterations during the progression of NAFLD promote NKT cell-dependent hepatic inflammation through changes in the CD1d-restricted repertoire of lipid antigens. In our work, we made the surprising observation that CD1d directly regulates hepatic lipid metabolism in an NKT cell-independent manner, both under constitutive conditions as well as in the context of NAFLD. These unexpected findings changed the scope of the proposed work and led to re-focusing on direct effects of CD1d on the progression of NAFLD. We could demonstrate that deletion of CD1d ameliorates accumulation of neutral lipids in the liver and inhibits liver inflammation and hepatic damage in the context of mouse models of NAFLD. Mechanistically, our work suggested that CD1d interferes with pathways of hepatic lipid secretion due to competition for enzymes involved in lipid transfer. Our work is the first to describe NKT cell-independent roles of CD1d in direct regulation of lipid metabolism and highlights CD1d as a novel target for therapeutic interference with metabolic inflammation in diseases such as NAFLD.
Publications
- Control of CD1d-restricted antigen presentation and inflammation by sphingomyelin. Nat Immunol. 2019 Oct 21
Melum E, Jiang X, Baker KD, Macedo MF, Fritsch J, Dowds CM, Wang J, Pharo A, Kaser A, Tan C, Pereira CS, Kelly SL, Duan J, Karlsen TH, Exley MA, Schütze S, Zajonc DM, Merrill AH, Schuchman EH, Zeissig S, Blumberg RS
(See online at https://doi.org/10.1038/s41590-019-0504-0) - Sterile activation of invariant natural killer T cells by ER- stressed antigen presenting cells. Proc Natl Acad Sci U S A. 2019 Nov
Bedard M, Shrestha D, Priestman DA, Wang Y, Schneider F, Matute JD, Iyer SS, Gileadi U, Prota G, Kandasamy M, Veerapen N, Besra G, Fritzsche M, Zeissig S, Shevchenko A, Christianson JC, Platt FM, Eggeling C, Blumberg RS, Salio M, Cerundolo V
(See online at https://doi.org/10.1073/pnas.1910097116)
