title: The Complement Anaphylatoxins C5a and C3a Suppress IFN-β Production in Response toListeria monocytogenesby Inhibition of the Cyclic Dinucleotide-Activated Cytosolic Surveillance Pathway.
abstract: Listeria monocytogenesis an intracellular Gram-positive bacterium that induces expression of type I IFNs (IFN-α/IFN-β) during infection. These cytokines are detrimental to the host during infection by priming leukocytes to undergoL. monocytogenes-mediated apoptosis. Our previous studies showed that C5aR1-/-and C3aR-/-mice are highly susceptible toL. monocytogenesinfection as a result of increased IFN-β-mediated apoptosis of major leukocyte cell populations, including CD4+and CD8+T cells. However, the mechanisms by which C3a and C5a modulate IFN-β expression duringL. monocytogenesinfection were not examined in these initial investigations. Accordingly, we report in this article that C5a and C3a suppress IFN-β production in response toL. monocytogenesvia cyclic di-AMP (c-di-AMP), a secondary messenger molecule ofL. monocytogenes, in J774A.1 macrophage-like cells and in bone marrow-derived dendritic cells (BMDCs). Moreover, C5a and C3a suppress IFN-β production by acting through their respective receptors, because no inhibition was seen in C5aR1-/-or C3aR-/-BMDCs, respectively. C5a and C3a suppress IFN-β production in a manner that is dependent on Bruton's tyrosine kinase, p38 MAPK, and TANK-binding kinase 1 (TBK1), as demonstrated by the individual use of Bruton's tyrosine kinase, p38 MAPK, and TBK1 inhibitors. Pretreatment of cells with C5a and C3a reduced the expression of the IFN-β signaling molecules DDX41, STING, phosphorylated TBK1, and phosphorylated p38 MAPK in wild-type BMDCs following treatment with c-di-AMP. Collectively, these data demonstrate that C3a and C5a, via direct signaling through their specific receptors, suppress IFN-β expression by modulation of a distinct innate cytosolic surveillance pathway involving DDX41, STING, and other downstream molecular targets ofL. monocytogenes-generated c-di-AMP.
authors.affiliation: Research Center for Immunology and Autoimmune Diseases, The Brown Foundation Institute of Molecular Medicine, University of Texas McGovern Medical School, Houston, TX 77030; and.
authors.forename: Stacey L
authors.initials: SL
authors.lastname: Mueller-Ortiz
authors.affiliation: Research Center for Immunology and Autoimmune Diseases, The Brown Foundation Institute of Molecular Medicine, University of Texas McGovern Medical School, Houston, TX 77030; and.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Calame
authors.affiliation: Research Center for Immunology and Autoimmune Diseases, The Brown Foundation Institute of Molecular Medicine, University of Texas McGovern Medical School, Houston, TX 77030; and.
authors.forename: Nancy
authors.identifier: 0000-0002-7103-0659
authors.initials: N
authors.lastname: Shenoi
authors.affiliation: Research Center for Immunology and Autoimmune Diseases, The Brown Foundation Institute of Molecular Medicine, University of Texas McGovern Medical School, Houston, TX 77030; and.
authors.forename: Yi-Dong
authors.initials: YD
authors.lastname: Li
authors.affiliation: Research Center for Immunology and Autoimmune Diseases, The Brown Foundation Institute of Molecular Medicine, University of Texas McGovern Medical School, Houston, TX 77030; and Rick.A.Wetsel@uth.tmc.edu.|Department of Biochemistry and Molecular Biology, University of Texas McGovern Medical School, Houston, TX 77030.
authors.forename: Rick A
authors.identifier: 0000-0003-4299-5096
authors.initials: RA
authors.lastname: Wetsel
mesh_terms: D000818:Animals; D015153:Blotting, Western; D015926:Complement C3a / Q000276:immunology* / Q000378:metabolism; D015936:Complement C5a / Q000276:immunology* / Q000378:metabolism; D000242:Cyclic AMP; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D007113:Immunity, Innate / Q000276:immunology*; D016899:Interferon-beta / Q000096:biosynthesis / Q000276:immunology*; D008089:Listeria monocytogenes; D008088:Listeriosis / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015398:Signal Transduction / Q000276:immunology*
chemical_list: D016899:Interferon-beta; D015926:Complement C3a; D015936:Complement C5a; D000242:Cyclic AMP