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

Abstract

Listeria monocytogenes (Lm) is an intracellular Gram-positive bacterium that induces expression of type I interferons (IFN-α/IFN-β) during infection. These cytokines are detrimental to the host during infection by priming leukocytes to undergo Lm-mediated apoptosis. Our previous studies showed that C5aR1−/− and C3aR−/− mice are highly susceptible to Lm infection due to elevated 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 Lm infection were not examined in these initial investigations. Accordingly, we report here that C5a and C3a suppress IFN-β production in response to Lm via c-di-AMP, a secondary messenger molecule of Lm, in both 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, as 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 (BTK), p38 MAPK, and TANK-Binding Kinase 1 (TBK1), as demonstrated by the individual use of BTK, p38 MAPK, and TBK1 inhibitors. Pre-treatment of cells with C5a and C3a reduced the expression of the IFN-β signaling molecules DDX41, STING, phosphorylated TBK1, and phosphorylated p38 MAPK in WT 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 Lm-generated c-di-AMP.

C3aR and C5aR1 act as key regulators of human and mouse β-cell function

“…An anti-apoptotic effect of a C5aR1 agonist in neurons has been reported [ 41 ], an unexpected function for an anaphylatoxin. Further evidence of a protective role for complement peptides is provided by a recent study in which C3a and C5a peptides reduced apoptosis of myeloid and lymphoid cells [ 42 ]. In the current study, activation of mouse and human islet C3aR and C5aR1 led to a robust reduction in apoptosis that had been induced by a cytokine cocktail or the saturated fatty acid palmitate.…”

Brain microvascular endothelial cells exhibit lower activation of the alternative complement pathway than glomerular microvascular endothelial cells

“…C3a (C3aR) and C5a (C5aR) are reported to be present on myeloid and lymphoid cells (23,24), platelets (25), HUVECs, and dermal microvascular endothelial cells (26).…”

Diverse Roles of DEAD/DEAH-Box Helicases in Innate Immunity and Diseases

“…Negative regulation of DDX41 is essential because excessive expression of type I interferons may cause various pathological conditions, such as systemic lupus erythematosus [122], or lymphocyte apoptosis during Listeria monocytogenes infection. Besides TRIM21, the complement anaphylatoxins C3a and C5a have also been reported to negatively regulate DDX41 by suppressing its expression [78].…”