biostudies-literatureMueller-Ortiz SLNIAID NIH HHS3237-3244https://www.ebi.ac.uk/biostudies/studies/S-EPMC5398560biostudies-literatureUnknown198(8)<i>Listeria monocytogenes</i> is 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 undergo <i>L. monocytogenes</i>-mediated apoptosis. Our previous studies showed that C5aR1^-/- and C3aR^-/- mice are highly susceptible to <i>L. monocytogenes</i> infection 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 during <i>L. monocytogenes</i> infection were not examined in these initial investigations. Accordingly, we report in this article that C5a and C3a suppress IFN-β production in response to <i>L. monocytogenes</i> via cyclic di-AMP (c-di-AMP), a secondary messenger molecule of <i>L. monocytogenes</i>, 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 of <i>L. monocytogenes</i>-generated c-di-AMP.Journal of immunology (Baltimore, Md. : 1950)The Complement Anaphylatoxins C5a and C3a Suppress IFN-β Production in Response to <i>Listeria monocytogenes</i> by Inhibition of the Cyclic Dinucleotide-Activated Cytosolic Surveillance Pathway.PMC5398560R01 AI025011Mueller-Ortiz SLLi YDWetsel RAShenoi NCalame DGfalseThe Complement Anaphylatoxins C5a and C3a Suppress IFN-β Production in Response to <i>Listeria monocytogenes</i> by Inhibition of the Cyclic Dinucleotide-Activated Cytosolic Surveillance Pathway.<i>Listeria monocytogenes</i> is 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 undergo <i>L. monocytogenes</i>-mediated apoptosis. Our previous studies showed that C5aR1^-/- and C3aR^-/- mice are highly susceptible to <i>L. monocytogenes</i> infection 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 during <i>L. monocytogenes</i> infection were not examined in these initial investigations. Accordingly, we report in this article that C5a and C3a suppress IFN-β production in response to <i>L. monocytogenes</i> via cyclic di-AMP (c-di-AMP), a secondary messenger molecule of <i>L. monocytogenes</i>, 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 of <i>L. monocytogenes</i>-generated c-di-AMP.2017-01-01T00:00:00Z2017 Apr2024-02-15T09:14:34.779Z2019-03-26T23:28:18ZS-EPMC53985602827513410.4049/jimmunol.1601420