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The Complement Anaphylatoxins C5a and C3a Suppress IFN- Production in Response to Listeria monocytogenes by Inhibition of the Cyclic Dinucleotide-Activated Cytosolic Surveillance Pathway

Mueller-Ortiz, SL;Calame, DG;Shenoi, N;Li, YD;Wetsel, RA;

Listeria monocytogenes is an intracellular Gram-positive bacterium that induces expression of type I IFNs (IFN-/IFN-) during infection. These cytokines are detrimental to the host during infection by priming leukocytes to undergo L. monocytogenes-mediated apoptosis. Our previous studies showed that C5aR1(-/-) and C3aR(-/-) mice are highly susceptible to L. monocytogenes infection as a result of increased IFN–mediated apoptosis of major leukocyte cell populations, including CD4(+) and CD8(+) T cells. However, the mechanisms by which C3a and C5a modulate IFN- expression during L. monocytogenes infection were not examined in these initial investigations. Accordingly, we report in this article that C5a and C3a suppress IFN- 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-derived dendritic cells (BMDCs). Moreover, C5a and C3a suppress IFN- production by acting through their respective receptors, because no inhibition was seen in C5aR1(-/-) or C3aR(-/-) BMDCs, respectively. C5a and C3a suppress IFN- 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- 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- expression by modulation of a distinct innate cytosolic surveillance pathway involving DDX41, STING, and other downstream molecular targets of L. monocytogenes-generated c-di-AMP.

  • PubMed ID: 28275134