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

J Immunol. 2017 Apr 15;198(8):3237-3244. doi: 10.4049/jimmunol.1601420. Epub 2017 Mar 8.


Listeria monocytogenes 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 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-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 L. monocytogenes 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 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-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 L. monocytogenes-generated c-di-AMP.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Blotting, Western
  • Complement C3a / immunology*
  • Complement C3a / metabolism
  • Complement C5a / immunology*
  • Complement C5a / metabolism
  • Cyclic AMP
  • Disease Models, Animal
  • Enzyme-Linked Immunosorbent Assay
  • Immunity, Innate / immunology*
  • Interferon-beta / biosynthesis
  • Interferon-beta / immunology*
  • Listeria monocytogenes
  • Listeriosis / immunology*
  • Listeriosis / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Signal Transduction / immunology*


  • Interferon-beta
  • Complement C3a
  • Complement C5a
  • Cyclic AMP