Tumurkhuu, G.Dagvadorj, J.Porritt, R. A.Crother, T. R.Shimada, K.Tarling, E. J.Erbay, E.Arditi, M.Chen, S.2019-02-212019-02-2120181550-4131http://hdl.handle.net/11693/49846Pathogen burden accelerates atherosclerosis, but the mechanisms remain unresolved. Activation of the NLRP3 inflammasome is linked to atherogenesis. Here we investigated whether Chlamydia pneumoniae (C.pn) infection engages NLRP3 in promoting atherosclerosis. C.pn potentiated hyperlipidemia-induced inflammasome activity in cultured macrophages and in foam cells in atherosclerotic lesions of Ldlr−/− mice. C.pn-induced acceleration of atherosclerosis was significantly dependent on NLRP3 and caspase-1. We discovered that C.pn-induced extracellular IL-1β triggers a negative feedback loop to inhibit GPR109a and ABCA1 expression and cholesterol efflux, leading to accumulation of intracellular cholesterol and foam cell formation. Gpr109a and Abca1 were both upregulated in plaque lesions in Nlrp3−/− mice in both hyperlipidemic and C.pn infection models. Mature IL-1β and cholesterol may compete for access to the ABCA1 transporter to be exported from macrophages. C.pn exploits this metabolic-immune crosstalk, which can be modulated by NLRP3 inhibitors to alleviate atherosclerosis. Infections can accelerate atherosclerosis, but the mechanisms remain unresolved. Tumurkhuu et al. show that C.pn infection-induced IL-1β institutes negative feedback to inhibit Gpr109a, ABCA1 expression, and cholesterol efflux, leading to accumulation of intracellular cholesterol. Mature IL-1β can use ABCA1 for secretion from macrophages to the detriment of cholesterol efflux.EnglishABCA1AspartateAtherosclerosisC. pneumoniaeCholesterol effluxFoam cellsGpr109aInterleukin-1 betaNiacinNlrp3Article10.1016/j.cmet.2018.05.0271932-7420