The novel function of SREBP‐1a in pathogenic defense mechanism of macrophages

SREBPs are important regulators of lipid metabolism. Here, we show SREBP‐1a also activates expression of inflammasome component Nlrp1a in mouse macrophages. In addition to lipogenesis, two hallmark inflammasome functions, activation of Caspase‐1 and IL‐1β secretion after LPS or bacterial challenge, are lower in SREBP‐1a deficient (1aDF) macrophages. 1aDF mice secrete less IL‐1β in response to LPS or cecal ligation and puncture (CLP), are resistant to endotoxic shock or severe inflammatory response syndrome, and are more susceptible to infection by S. typhimurium . Thus, SREBP‐1a connects lipid metabolism to the innate immune system. Moreover, we suggest SREBP‐1a regulates an innate defense response against pathogen attack through phagocytotic function and survival of macrophages. Opsonized target‐mediated phagocytosis was decreased in 1aDF macrophages and SREBP‐1a is also involved in the macrophage survival response after exposure to bacterial toxins through regulation of the anti‐apototic gene Api6. Api6 gene expression is reduced significantly in the 1aDF macrophages and re‐introduction of Api6 expression through an exogenous expression vector in the 1aDF macrophages reverses the apoptosis defect. Our results demonstrate that APi6 is a new direct target of SREBP‐1a in macrophages and as such is an important component that links lipid metabolism to the macrophage response to pathogen challenge.