Complement Receptor 3-Mediated Inhibition of Inflammasome Priming by Ras GTPase-Activating Protein During Francisella tularensis Phagocytosis by Human Mononuclear Phagocytes.

Ky V Hoang,Heather Marie Curry,Mikhail A Gavrilin,Murugesan V S Rajaram,Mark D Wewers,Larry S Schlesinger

doi:10.3389/fimmu.2018.00561

Abstract

Francisella tularensis is a remarkably infectious facultative intracellular bacterium of macrophages that causes tularemia. Early evasion of host immune responses contributes to the success of F. tularensis as a pathogen. F. tularensis entry into human monocytes and macrophages is mediated by the major phagocytic receptor, complement receptor 3 (CR3, CD11b/CD18). We recently determined that despite a significant increase in macrophage uptake following C3 opsonization of the virulent Type A F. tularensis spp. tularensis Schu S4, this phagocytic pathway results in limited pro-inflammatory cytokine production. Notably, MAP kinase/ERK activation is suppressed immediately during C3-opsonized Schu S4-CR3 phagocytosis. A mathematical model of CR3-TLR2 crosstalk predicted early involvement of Ras GTPase-activating protein (RasGAP) in immune suppression by CR3. Here, we link CR3-mediated uptake of opsonized Schu S4 by human monocytes and macrophages with inhibition of early signal 1 inflammasome activation, evidenced by limited caspase-1 cleavage and IL-18 release. This inhibition is due to increased RasGAP activity, leading to a reduction in the Ras-ERK signaling cascade upstream of the early inflammasome activation event. Thus, our data uncover a novel signaling pathway mediated by CR3 following engagement of opsonized virulent F. tularensis to limit inflammasome activation in human phagocytic cells, thereby contributing to evasion of the host innate immune system.

Highlights

Francisella tularensis is a facultative intracellular bacterium that causes tularemia, a zoonotic disease that is transmitted through aerosol or arthropod vectors [1,2,3,4]
Activation of the NLRP3 inflammasome in monocytes, macrophages, dendritic cells, and microglial cells requires two steps: the first priming step is mediated by pathogenassociated molecular patterns (PAMPs)-pattern recognition receptors (PRRs) and the second step mediated by various bacterial toxins or ATP, and potassium efflux, leads to inflammasome assembly and activation [18,19,20,21]
Inflammasome priming is dependent on ERK signaling [16], and we have previo usly found that serum opsonization of Schu S4 downregulates ERK activation within 5 min of Francisella phagocytosis [54]

Summary

Introduction

Francisella tularensis is a facultative intracellular bacterium that causes tularemia, a zoonotic disease that is transmitted through aerosol or arthropod vectors [1,2,3,4]. Compared to the nonpathogenic subspecies [e.g., Francisella novicida (Fn)], the Schu S4 strain leads to significantly reduced pro-inflammatory cytokine production [6,7,8,9]. This reduced response during the early stage of infection is critical for establishment of infection in human macrophages. As a member of the NOD-like receptor family, the most widely studied NLRP3 inflammasome responds to a variety of structurally and chemically diverse molecules [12, 13], and TLR signaling and inflammasome activation often crosstalk during microbial infection [14,15,16,17]. Recent studies demonstrate that NLRP3 inflammasome priming by LPS is dependent on MAP kinase (MAPK)/ ERK activation [24] and proteasome function [16, 24]

Methods

Results

Conclusion