The pro-inflammatory effect of triglyceride on human CD4+ T cells and experimental autoimmune uveitis

Aberrant lipid metabolism plays a role in inflammation and progression of autoimmune diseases but the definite mechanism remains unclear. In this study we investigate lipidomic profiles in Behçet's disease (BD) and the role of triglyceride (TAG) in the pathogenesis of autoimmune uveitis. Lipidomics revealed a distinct lipid metabolite profile including increased TAG metabolites in plasma of active BD patients. TAG could stimulate the proliferation, IL-17 and IFN-γ expression by CD4+ T cells and Th1, Th17 cell differentiation in vitro, but did not influence neutrophils. A922500 inhibited the TAG generation, ameliorated the EAU severity, decreased Th17 frequency and IL-17 expression by CD4+ T cells in vivo. The proteomocis analysis showed an up-regulation of apoptosis-related protein, Pik3r2, in CD4+ T cells from A922500-treated mice. In conclusion, TAG can stimulate human CD4+ T cells and the inhibition of its generation could significantly ameliorate EAU activity in association with down-regulated Th17 cell response.

 

Comments：

The study investigated the role of aberrant lipid metabolism in Behçet's disease (BD) and autoimmune uveitis. The researchers conducted lipidomic profiling and found a distinct lipid metabolite profile in plasma of active BD patients, including increased triglyceride (TAG) metabolites. They further investigated the role of TAG in the pathogenesis of autoimmune uveitis and found that TAG can stimulate the proliferation, IL-17 and IFN-γ expression by CD4+ T cells and Th1, Th17 cell differentiation in vitro, but did not influence neutrophils.

The researchers then tested the effects of A922500, a drug that inhibits TAG generation, on experimental autoimmune uveitis (EAU) in mice. They found that A922500 inhibited TAG generation, ameliorated the severity of EAU, decreased Th17 frequency and IL-17 expression by CD4+ T cells in vivo. The proteomic analysis showed an up-regulation of apoptosis-related protein, Pik3r2, in CD4+ T cells from A922500-treated mice.

The study suggests that aberrant lipid metabolism, specifically increased TAG levels, plays a role in the pathogenesis of BD and autoimmune uveitis by stimulating CD4+ T cells and promoting Th1 and Th17 cell differentiation. Inhibition of TAG generation using A922500 can ameliorate EAU severity, possibly by down-regulating Th17 cell response and promoting apoptosis-related protein expression.

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S2674	A922500	A922500 (DGAT-1 Inhibitor 4a) is an inhibitor for human and mouse DGAT-1 with IC50 of 7 nM and 24 nM, respectively, good selectivity over related acyltransferases, hERG, and a panel of anti-targets.

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Transferase Acyltransferase