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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.

ABSTRACT: 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.

SUBMITTER: Mueller-Ortiz SL

PROVIDER: S-EPMC5398560 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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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.

Mueller-Ortiz Stacey L SL Calame Daniel G DG Shenoi Nancy N Li Yi-Dong YD Wetsel Rick A RA

Journal of immunology (Baltimore, Md. : 1950) 20170308 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 po ...[more]

PMID: 28275134

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Project description:BACKGROUND:Hepatitis B virus (HBV) infections represent a global health problem and chronic hepatitis B (CHB) leads to liver cirrhosis and hepatocellular carcinoma. Thus, timely diagnosis of hepatitis B is crucial to ensure adequate treatment. We developed a powerful and rapid whole blood-based cytokine release assay assessing cellular immune responses to HBV antigens. IL-2 and IFN? release in this assay depicts hepatitis B vaccination status. Of note, CHB goes along with elevated C5a concentrations in plasma. We aim at mimicking the proinflammatory microenvironment associated with HBV infection to enhance the diagnostic quality of our HBV specific cytokine release assay. We specifically investigated the potential of the complement factors C3a and C5a as costimulators and analyzed their potential effects on activation marker expression on T cells and antigen presenting cells. RESULTS:Whole blood from 87 healthy individuals (n?=?59 hepatitis B vaccinated, n?=?28 unvaccinated) was stimulated with HBV surface antigen (HBsAg) in presence or absence of C3a or C5a, respectively. Further, C3a and C5a were used in combination to investigate potential synergistic effects. IL-2 and IFN? levels in plasma were quantified using ELISA. Complement factor C5a specifically enhances HBsAg-mediated IL-2 (690.3?±?195.4 pg/ml vs. 789.4?±?216.5 pg/ml) and IFN? (146.0?±?43.1 pg/ml vs. 336.7?±?67.9 pg/ml) responses in whole blood. Similar cytokine levels were measured when both C3a and C5a were used. With a diagnostic specificity of 90% the IFN? release assay reached a diagnostic sensitivity of 49.2% upon whole blood stimulation with HBsAg alone, but of 78.9% when HBsAg was combined with C3a and C5a. CONCLUSIONS:Innate signals mediated via complement pathways contribute to HBV-specific cellular immune responses. The massively improved diagnostic sensitivity of the IFN? release assay after addition of C3a and C5a demonstrates that these effects render whole blood-based cytokine release assays even more potent as screening tools in HBV immunology and HBV vaccination studies.

Project description:Early-onset pre-eclampsia is characterized by decreased placental perfusion, new-onset hypertension, angiogenic imbalance, and endothelial dysfunction associated with excessive activation of the innate immune complement system. Although our previous studies demonstrated that inhibition of complement activation attenuates placental ischemia-induced hypertension using the rat reduced uterine perfusion pressure (RUPP) model, the important product(s) of complement activation has yet to be identified. We hypothesized that antagonism of receptors for complement activation products C3a and C5a would improve vascular function and attenuate RUPP hypertension. On gestational day (GD) 14, rats underwent sham surgery or vascular clip placement on ovarian arteries and abdominal aorta (RUPP). Rats were treated once daily with the C5a receptor antagonist (C5aRA), PMX51 (acetyl-F-[Orn-P-(D-Cha)-WR]), the C3a receptor antagonist (C3aRA), SB290157 (N(2)-[(2,2-diphenylethoxy)acetyl]-l-arginine), or vehicle from GD 14-18. Both the C3aRA and C5aRA attenuated placental ischemia-induced hypertension without affecting the decreased fetal weight or decreased concentration of free circulating vascular endothelial growth factor (VEGF) also present in this model. The C5aRA, but not the C3aRA, attenuated placental ischemia-induced increase in heart rate and impaired endothelial-dependent relaxation. The C3aRA abrogated the acute pressor response to C3a peptide injection, but it also unexpectedly attenuated the placental ischemia-induced increase in C3a, suggesting nonreceptor-mediated effects. Overall, these results indicate that both C3a and C5a are important products of complement activation that mediate the hypertension regardless of the reduction in free plasma VEGF. The mechanism by which C3a contributes to placental ischemia-induced hypertension appears to be distinct from that of C5a, and management of pregnancy-induced hypertension is likely to require a broad anti-inflammatory approach.

Dataset Information

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

Publications

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.

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