{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T20:19:15Z","timestamp":1789676355824,"version":"4.0.1"},"reference-count":41,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2017,4,1]],"date-time":"2017-04-01T00:00:00Z","timestamp":1491004800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2017,4,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Listeria monocytogenes is an intracellular Gram-positive bacterium that induces expression of type I IFNs (IFN-\u03b1\/IFN-\u03b2) during infection. These cytokines are detrimental to the host during infection by priming leukocytes to undergo L. monocytogenes\u2013mediated apoptosis. Our previous studies showed that C5aR1\u2212\/\u2212 and C3aR\u2212\/\u2212 mice are highly susceptible to L. monocytogenes infection as a result of increased IFN-\u03b2\u2013mediated apoptosis of major leukocyte cell populations, including CD4+ and CD8+ T cells. However, the mechanisms by which C3a and C5a modulate IFN-\u03b2 expression during L. monocytogenes infection were not examined in these initial investigations. Accordingly, we report in this article that C5a and C3a suppress IFN-\u03b2 production in response to L. monocytogenes via cyclic di-AMP (c-di-AMP), a secondary messenger molecule of L. monocytogenes, in J774A.1 macrophage-like cells and in bone marrow\u2013derived dendritic cells (BMDCs). Moreover, C5a and C3a suppress IFN-\u03b2 production by acting through their respective receptors, because no inhibition was seen in C5aR1\u2212\/\u2212 or C3aR\u2212\/\u2212 BMDCs, respectively. C5a and C3a suppress IFN-\u03b2 production in a manner that is dependent on Bruton\u2019s tyrosine kinase, p38 MAPK, and TANK-binding kinase 1 (TBK1), as demonstrated by the individual use of Bruton\u2019s tyrosine kinase, p38 MAPK, and TBK1 inhibitors. Pretreatment of cells with C5a and C3a reduced the expression of the IFN-\u03b2 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-\u03b2 expression by modulation of a distinct innate cytosolic surveillance pathway involving DDX41, STING, and other downstream molecular targets of L. monocytogenes\u2013generated c-di-AMP.<\/jats:p>","DOI":"10.4049\/jimmunol.1601420","type":"journal-article","created":{"date-parts":[[2017,3,9]],"date-time":"2017-03-09T01:55:35Z","timestamp":1489024535000},"page":"3237-3244","source":"Crossref","is-referenced-by-count":30,"title":["The Complement Anaphylatoxins C5a and C3a Suppress IFN-\u03b2 Production in Response to <i>Listeria monocytogenes<\/i> by Inhibition of the Cyclic Dinucleotide\u2013Activated Cytosolic Surveillance Pathway"],"prefix":"10.1093","volume":"198","author":[{"given":"Stacey L","family":"Mueller-Ortiz","sequence":"first","affiliation":[{"name":"Research Center for Immunology and Autoimmune Diseases, The Brown Foundation Institute of Molecular Medicine, University of Texas McGovern Medical School , Houston, TX 77030"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel G","family":"Calame","sequence":"additional","affiliation":[{"name":"Research Center for Immunology and Autoimmune Diseases, The Brown Foundation Institute of Molecular Medicine, University of Texas McGovern Medical School , Houston, TX 77030"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7103-0659","authenticated-orcid":false,"given":"Nancy","family":"Shenoi","sequence":"additional","affiliation":[{"name":"Research Center for Immunology and Autoimmune Diseases, The Brown Foundation Institute of Molecular Medicine, University of Texas McGovern Medical School , Houston, TX 77030"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Dong","family":"Li","sequence":"additional","affiliation":[{"name":"Research Center for Immunology and Autoimmune Diseases, The Brown Foundation Institute of Molecular Medicine, University of Texas McGovern Medical School , Houston, TX 77030"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4299-5096","authenticated-orcid":false,"given":"Rick A","family":"Wetsel","sequence":"additional","affiliation":[{"name":"Research Center for Immunology and Autoimmune Diseases, The Brown Foundation Institute of Molecular Medicine, University of Texas McGovern Medical School , Houston, TX 77030"},{"name":"Department of Biochemistry and Molecular Biology, University of Texas McGovern Medical School , Houston, TX 77030"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2017,4,15]]},"reference":[{"key":"2025030615091281200_r1","doi-asserted-by":"crossref","first-page":"2211","DOI":"10.1056\/NEJMra1213566","article-title":"Pregnancy and infection","volume":"370","author":"Kourtis","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"2025030615091281200_r2","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1515\/jpm.2011.035","article-title":"Listeriosis in human pregnancy: a systematic review","volume":"39","author":"Lamont","year":"2011","journal-title":"J. Perinat. Med."},{"key":"2025030615091281200_r3","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1016\/S1473-3099(14)70870-9","article-title":"The global burden of listeriosis: a systematic review and meta-analysis","volume":"14","author":"Maertens de Noordhout","year":"2014","journal-title":"Lancet Infect. Dis."},{"key":"2025030615091281200_r4","first-page":"113","volume-title":"Contemporary Immunology: Therapeutic Interventions in the Complement System.","author":"Wetsel","year":"2000"},{"key":"2025030615091281200_r5","doi-asserted-by":"crossref","first-page":"2753","DOI":"10.1016\/j.molimm.2009.04.027","article-title":"The role of the anaphylatoxins in health and disease","volume":"46","author":"Klos","year":"2009","journal-title":"Mol. Immunol."},{"key":"2025030615091281200_r6","doi-asserted-by":"crossref","first-page":"1278","DOI":"10.4049\/jimmunol.1302787","article-title":"The receptor for the complement C3a anaphylatoxin (C3aR) provides host protection against Listeria monocytogenes-induced apoptosis","volume":"193","author":"Mueller-Ortiz","year":"2014","journal-title":"J. Immunol."},{"key":"2025030615091281200_r7","doi-asserted-by":"crossref","first-page":"5099","DOI":"10.4049\/jimmunol.1401750","article-title":"The C5a anaphylatoxin receptor (C5aR1) protects against Listeria monocytogenes infection by inhibiting type 1 IFN expression","volume":"193","author":"Calame","year":"2014","journal-title":"J. Immunol."},{"key":"2025030615091281200_r8","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1084\/jem.20040976","article-title":"Mice lacking the type I interferon receptor are resistant to Listeria monocytogenes","volume":"200","author":"Auerbuch","year":"2004","journal-title":"J. Exp. Med."},{"key":"2025030615091281200_r9","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1084\/jem.20040769","article-title":"Type I interferon sensitizes lymphocytes to apoptosis and reduces resistance to Listeria infection","volume":"200","author":"Carrero","year":"2004","journal-title":"J. Exp. Med."},{"key":"2025030615091281200_r10","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1084\/jem.20040712","article-title":"Type I interferon production enhances susceptibility to Listeria monocytogenes infection","volume":"200","author":"O\u2019Connell","year":"2004","journal-title":"J. Exp. Med."},{"key":"2025030615091281200_r11","doi-asserted-by":"crossref","first-page":"6522","DOI":"10.4049\/jimmunol.169.11.6522","article-title":"Production of type I IFN sensitizes macrophages to cell death induced by Listeria monocytogenes","volume":"169","author":"Stockinger","year":"2002","journal-title":"J. Immunol."},{"key":"2025030615091281200_r12","doi-asserted-by":"crossref","first-page":"7404","DOI":"10.1073\/pnas.82.21.7404","article-title":"Requirement of endogenous interferon-gamma production for resolution of Listeria monocytogenes infection","volume":"82","author":"Buchmeier","year":"1985","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025030615091281200_r13","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/1074-7613(95)90163-9","article-title":"Specific immunity to Listeria monocytogenes in the absence of IFN gamma","volume":"3","author":"Harty","year":"1995","journal-title":"Immunity"},{"key":"2025030615091281200_r14","doi-asserted-by":"crossref","first-page":"1742","DOI":"10.1126\/science.8456301","article-title":"Immune response in mice that lack the interferon-gamma receptor","volume":"259","author":"Huang","year":"1993","journal-title":"Science"},{"key":"2025030615091281200_r15","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1084\/jem.20091746","article-title":"Induction of IFN-alphabeta enables Listeria monocytogenes to suppress macrophage activation by IFN-gamma","volume":"207","author":"Rayamajhi","year":"2010","journal-title":"J. Exp. Med."},{"key":"2025030615091281200_r16","doi-asserted-by":"crossref","first-page":"11386","DOI":"10.1073\/pnas.0403215101","article-title":"A specific gene expression program triggered by Gram-positive bacteria in the cytosol","volume":"101","author":"McCaffrey","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025030615091281200_r17","doi-asserted-by":"crossref","first-page":"1602","DOI":"10.4049\/jimmunol.174.3.1602","article-title":"Immune activation of type I IFNs by Listeria monocytogenes occurs independently of TLR4, TLR2, and receptor interacting protein 2 but involves TNFR-associated NF kappa B kinase-binding kinase 1","volume":"174","author":"O\u2019Connell","year":"2005","journal-title":"J. Immunol."},{"key":"2025030615091281200_r18","doi-asserted-by":"crossref","first-page":"7416","DOI":"10.4049\/jimmunol.173.12.7416","article-title":"IFN regulatory factor 3-dependent induction of type I IFNs by intracellular bacteria is mediated by a TLR- and Nod2-independent mechanism","volume":"173","author":"Stockinger","year":"2004","journal-title":"J. Immunol."},{"key":"2025030615091281200_r19","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.1016\/j.celrep.2015.01.039","article-title":"Bruton\u2019s tyrosine kinase phosphorylates DDX41 and activates its binding of dsDNA and STING to initiate type 1 interferon response","volume":"10","author":"Lee","year":"2015","journal-title":"Cell Rep."},{"key":"2025030615091281200_r20","doi-asserted-by":"crossref","first-page":"1155","DOI":"10.1038\/ni.2460","article-title":"The helicase DDX41 recognizes the bacterial secondary messengers cyclic di-GMP and cyclic di-AMP to activate a type I interferon immune response","volume":"13","author":"Parvatiyar","year":"2012","journal-title":"Nat. Immunol."},{"key":"2025030615091281200_r21","doi-asserted-by":"crossref","first-page":"788","DOI":"10.1038\/nature08476","article-title":"STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity","volume":"461","author":"Ishikawa","year":"2009","journal-title":"Nature"},{"key":"2025030615091281200_r22","doi-asserted-by":"crossref","first-page":"688","DOI":"10.1128\/IAI.00999-10","article-title":"The N-ethyl-N-nitrosourea-induced Goldenticket mouse mutant reveals an essential function of Sting in the in vivo interferon response to Listeria monocytogenes and cyclic dinucleotides","volume":"79","author":"Sauer","year":"2011","journal-title":"Infect. Immun."},{"key":"2025030615091281200_r23","doi-asserted-by":"crossref","first-page":"13861","DOI":"10.1073\/pnas.202476699","article-title":"Innate recognition of bacteria by a macrophage cytosolic surveillance pathway","volume":"99","author":"O\u2019Riordan","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025030615091281200_r24","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.immuni.2005.12.003","article-title":"Recognition of cytosolic DNA activates an IRF3-dependent innate immune response","volume":"24","author":"Stetson","year":"2006","journal-title":"Immunity"},{"key":"2025030615091281200_r25","doi-asserted-by":"crossref","first-page":"1703","DOI":"10.1126\/science.1189801","article-title":"c-di-AMP secreted by intracellular Listeria monocytogenes activates a host type I interferon response","volume":"328","author":"Woodward","year":"2010","journal-title":"Science"},{"key":"2025030615091281200_r26","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1038\/nature10429","article-title":"STING is a direct innate immune sensor of cyclic di-GMP","volume":"478","author":"Burdette","year":"2011","journal-title":"Nature"},{"key":"2025030615091281200_r27","doi-asserted-by":"crossref","first-page":"1654","DOI":"10.15252\/embj.201488029","article-title":"Listeria monocytogenes induces IFN\u03b2 expression through an IFI16-, cGAS- and STING-dependent pathway","volume":"33","author":"Hansen","year":"2014","journal-title":"EMBO J."},{"key":"2025030615091281200_r28","doi-asserted-by":"crossref","first-page":"ra20","DOI":"10.1126\/scisignal.2002521","article-title":"STING specifies IRF3 phosphorylation by TBK1 in the cytosolic DNA signaling pathway","volume":"5","author":"Tanaka","year":"2012","journal-title":"Sci. Signal."},{"key":"2025030615091281200_r29","doi-asserted-by":"crossref","first-page":"4591","DOI":"10.4049\/jimmunol.157.10.4591","article-title":"Antisense homology boxes in C5a receptor and C5a anaphylatoxin: a new method for identification of potentially active peptides","volume":"157","author":"Baranyi","year":"1996","journal-title":"J. Immunol."},{"key":"2025030615091281200_r30","doi-asserted-by":"crossref","first-page":"4159","DOI":"10.1021\/jm201609k","article-title":"De novo peptide design with C3a receptor agonist and antagonist activities: theoretical predictions and experimental validation","volume":"55","author":"Bellows-Peterson","year":"2012","journal-title":"J. Med. Chem."},{"key":"2025030615091281200_r31","doi-asserted-by":"crossref","first-page":"5406","DOI":"10.4049\/jimmunol.165.10.5406","article-title":"Cutting edge: targeted disruption of the C3a receptor gene demonstrates a novel protective anti-inflammatory role for C3a in endotoxin-shock","volume":"165","author":"Kildsgaard","year":"2000","journal-title":"J. Immunol."},{"key":"2025030615091281200_r32","doi-asserted-by":"crossref","first-page":"1907","DOI":"10.1016\/j.molimm.2007.10.037","article-title":"Disruption of the C5a receptor gene increases resistance to acute Gram-negative bacteremia and endotoxic shock: opposing roles of C3a and C5a","volume":"45","author":"Hollmann","year":"2008","journal-title":"Mol. Immunol."},{"key":"2025030615091281200_r33","doi-asserted-by":"crossref","first-page":"e15567","DOI":"10.1371\/journal.pone.0015567","article-title":"A fluorescence reporter model defines \u201cTip-DCs\u201d as the cellular source of interferon \u03b2 in murine listeriosis","volume":"5","author":"Dresing","year":"2010","journal-title":"PLoS One"},{"key":"2025030615091281200_r34","doi-asserted-by":"crossref","first-page":"e1000355","DOI":"10.1371\/journal.ppat.1000355","article-title":"Characterization of the interferon-producing cell in mice infected with Listeria monocytogenes","volume":"5","author":"Stockinger","year":"2009","journal-title":"PLoS Pathog."},{"key":"2025030615091281200_r35","doi-asserted-by":"crossref","first-page":"959","DOI":"10.1038\/ni.2091","article-title":"The helicase DDX41 senses intracellular DNA mediated by the adaptor STING in dendritic cells","volume":"12","author":"Zhang","year":"2011","journal-title":"Nat. Immunol."},{"key":"2025030615091281200_r36","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.imbio.2011.07.033","article-title":"Functional modulation of human monocytes derived DCs by anaphylatoxins C3a and C5a","volume":"217","author":"Li","year":"2012","journal-title":"Immunobiology"},{"key":"2025030615091281200_r37","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1016\/j.immuni.2008.02.001","article-title":"Locally produced complement fragments C5a and C3a provide both costimulatory and survival signals to naive CD4+ T cells","volume":"28","author":"Strainic","year":"2008","journal-title":"Immunity"},{"key":"2025030615091281200_r38","doi-asserted-by":"crossref","first-page":"3827","DOI":"10.4049\/jimmunol.0803055","article-title":"C3a and C5a are chemotactic factors for human mesenchymal stem cells, which cause prolonged ERK1\/2 phosphorylation","volume":"182","author":"Schraufstatter","year":"2009","journal-title":"J. Immunol."},{"key":"2025030615091281200_r39","doi-asserted-by":"crossref","first-page":"1085","DOI":"10.1016\/j.celrep.2014.02.014","article-title":"Autocrine effects of tumor-derived complement","volume":"6","author":"Cho","year":"2014","journal-title":"Cell Rep."},{"key":"2025030615091281200_r40","doi-asserted-by":"crossref","first-page":"1603","DOI":"10.1084\/jem.20021845","article-title":"Bruton\u2019s tyrosine kinase is required for lipopolysaccharide-induced tumor necrosis factor alpha production","volume":"197","author":"Horwood","year":"2003","journal-title":"J. Exp. Med."},{"key":"2025030615091281200_r41","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1038\/nchembio.481","article-title":"Specific Btk inhibition suppresses B cell- and myeloid cell-mediated arthritis","volume":"7","author":"Di Paolo","year":"2011","journal-title":"Nat. Chem. Biol."}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/198\/8\/3237\/61449330\/1601420.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/198\/8\/3237\/61449330\/1601420.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,6]],"date-time":"2025-03-06T17:23:35Z","timestamp":1741281815000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/198\/8\/3237\/7954919"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,4]]},"references-count":41,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2017,4,15]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.1601420","relation":{},"ISSN":["0022-1767","1550-6606"],"issn-type":[{"value":"0022-1767","type":"print"},{"value":"1550-6606","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2017,4]]},"published":{"date-parts":[[2017,4]]}}}