Bidirectional Crosstalk between C5a Receptors and the NLRP3 Inflammasome in Macrophages and Monocytes.

Mikel D Haggadone,Jamison J Grailer,Fatemeh Fattahi,Peter A Ward,Firas S Zetoune

doi:10.1155/2016/1340156

Abstract

C5a is an inflammatory mediator generated by complement activation that positively regulates various arms of immune defense, including Toll-like receptor 4 (TLR4) signaling. The NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome is activated by pathogen products and cellular/tissue damage products and is a major contributor of IL-1β. In this study, we investigate whether C5a modulates lipopolysaccharide- (LPS-) induced NLRP3 inflammasome activation in myeloid cells. Appearance of plasma IL-1β during endotoxemia was reduced in C5aR1−/− mice when compared to wild-type mice. In vitro, C5a significantly enhanced LPS-induced production of IL-1β in bone marrow Ly6C-high inflammatory monocytes, accompanied by augmented intracellular pro-IL-1β expression. This effect was abolished during p38 blockade by SB 203580 and in the absence of C5aR1. Conversely, C5a suppressed LPS-induced macrophage production of IL-1β, which was accompanied by attenuated levels of pro-IL-1β, NLRP3, and caspase-1 expression. C5a's suppressive effects were negated during phosphoinositide 3-kinase (PI3K) inhibition by wortmannin but were largely preserved in the absence of C5aR1. Thus, C5a bidirectionally amplifies TLR4-mediated NLRP3 inflammasome activation in monocytes while suppressing this pathway in macrophages. However, as C5aR1 deficiency attenuates the IL-1β response to LPS challenge in vivo, our results suggest overall that C5a augments physiologic inflammasome responses.

Highlights

Myeloid-derived, innate inflammatory cells provide early defense against invading pathogens by activating a diverse array of protective immune mechanisms
As p38 signaling has been shown to potentiate IL-1 and tumor necrosis factor (TNF)-α production in activated monocytes [26] and to mediate C5a-enhanced monocyte IL-6 secretion induced by LPS [15], we investigated whether this pathway assumed a functional role downstream of C5a to enhance the NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome response
The results of our study suggest that C5a-C5aR1 interactions are critical for enhancing the innate IL-1β response during LPS-induced endotoxemia

Summary

Introduction

Myeloid-derived, innate inflammatory cells provide early defense against invading pathogens by activating a diverse array of protective immune mechanisms Underlying these cells’ effector functions are the pattern recognition receptors (PRRs), which detect repeating molecular motifs inherent to various pathogens (pathogen-associated molecular patterns (PAMPs)) and danger-associated molecular patterns (DAMPs) generated as a result of tissue and cellular damage. An important downstream target of TLR4 is the NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome [1] This multiprotein complex, responsible for cell pyroptosis and the caspase-1-dependent processing of pro-IL-1β and pro-IL-18 to their biologically active forms [2], has been shown to play a prominent role in regulating both chronic and acute inflammation as a responder to cell damage and stress. Signal 2 activates the inflammasome by inducing cationic fluxes (K+ efflux and elevated intracellular Ca+2), mitochondrial and lysosomal

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Conclusion