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      Chlamydia pneumoniae hijacks a host auto-regulatory IL-1β loop to drive foam cell formation and accelerate atherosclerosis

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          SUMMARY

          Pathogen burden accelerate 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 cross talk, which can be modulated by NLRP3 inhibitors to alleviate atherosclerosis.

          eTOC

          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 at the detriment of cholesterol efflux.

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          Author and article information

          Journal
          101233170
          32527
          Cell Metab
          Cell Metab.
          Cell metabolism
          1550-4131
          1932-7420
          19 June 2018
          21 June 2018
          04 September 2018
          04 September 2019
          : 28
          : 3
          : 432-448.e4
          Affiliations
          [1 ]Departments of Pediatrics and Medicine, Division of Infectious Diseases and Immunology, and Infectious and Immunologic Diseases Research Center (IIDRC), Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA
          [2 ]David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA.
          [3 ]Department of Medicine, Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA
          [4 ]Department of Medicine, and Department of Biomedical Sciences, Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA (current affiliation)
          [5 ]Department of Molecular Biology and Genetics and National Nanotechnology Center, Bilkent University, Ankara, Turkey
          Author notes
          []Lead Contact and corresponding author. Moshe.Arditi@ 123456cshs.org
          [*]

          these authors contributed equally

          [#]

          these senior authors contributed equally.

          Article
          PMC6125162 PMC6125162 6125162 nihpa976312
          10.1016/j.cmet.2018.05.027
          6125162
          29937375
          b3ebab07-c72b-4160-b0ae-136e87b88608
          History
          Categories
          Article

          aspartate,Nlrp3,oxLDL,ABCA1,Gpr109a,cholesterol efflux,niacin,atherosclerosis, C. pneumoniae ,Interleukin-1 beta,foam cells,macrophage

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