OX40 Regulates Both Innate and Adaptive Immunity and Promotes Nonalcoholic Steatohepatitis

摘要

Both innate and adaptive immune cells are involvedin the pathogenesis of nonalcoholic steatohepatitis(NASH), but the crosstalk between innate and adaptiveimmunity is largely unknown. Here we show thatcompared with WT mice, OX40 / mice exhibitdecreased liver fat accumulation, lobular inflammation,and focal necrosis after feeding with diets thatinduce NASH. Mechanistically, OX40 deficiency suppressesTh1 and Th17 differentiation, and OX40 deficiencyin T cells inhibits monocyte migration, antigenpresentation, and M1 polarization. Soluble OX40stimulation alone upregulates antigen presentation,chemokine receptor expression, and proinflammatorycytokine secretion by liver monocytes. Furthermore,plasma soluble OX40 levels are positivelyassociated with NASH in humans, suggesting clinicalrelevance of the findings. In conclusion, we show amechanism for T cell regulation of innate immunecells. OX40 is a key regulator of both intrahepaticinnate and adaptive immunity, generates two-waysignals, and promotes both proinflammatory monocyteand macrophage and T cell function, resultingin NASH development.