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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
- Source :
- The Journal of Immunology. 198:3237-3244
- Publication Year :
- 2017
- Publisher :
- The American Association of Immunologists, 2017.
-
Abstract
- 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.
- Subjects :
- 0301 basic medicine
Cell signaling
Kinase
Immunology
chemical and pharmacologic phenomena
Biology
Cell biology
03 medical and health sciences
030104 developmental biology
0302 clinical medicine
TANK-binding kinase 1
Second messenger system
Immunology and Allergy
Anaphylatoxin
Signal transduction
Receptor
Tyrosine kinase
030215 immunology
Subjects
Details
- ISSN :
- 15506606 and 00221767
- Volume :
- 198
- Database :
- OpenAIRE
- Journal :
- The Journal of Immunology
- Accession number :
- edsair.doi...........4653689f88e9268bdb7de8e0ad8c016b