G Protein-Coupled Receptor 120 Mediates Host Defense against Clostridium perfringens Infection through Regulating NOD-like Receptor Family Pyrin Domain-Containing 3 Inflammasome Activation

Abstract

Clostridium perfringens is a major cause of infectious foodborne disease, frequently associated with the consumption of raw and undercooked food. Despite intensive studies on clarifying C. perfringens pathogenesis, the molecular mechanisms of host− pathogen interactions remain poorly understood. In soft tissue and mucosal infection models, Gpr120 -/mice, G protein-coupled receptor 120 (GPR120), are more susceptible to C. perfringens infection. Gpr120 deficiency leads to a low survival rate (30 and 10%, p < 0.01), more bacterial loads in the muscle (2.26 × 10 8 ± 2.08 × 10 8 CFUs/g, p < 0.01), duodenum (2.80 × 10 7 ± 1.61 × 10 7 CFUs/g, p < 0.01), cecum (2.50 × 10 8 ± 2.05 × 10 8 CFUs/g, p < 0.01), and MLN (1.23 × 10 6 ± 8.06 × 10 5 CFUs/g, p < 0.01), less IL-18 production in the muscle (8.54 × 10 3 ± 1.20 × 10 3 pg/g, p < 0.01), duodenum (3.34 × 10 3 ± 2.46 × 10 2 pg/g, p < 0.01), and cecum (3.81 × 10 3 ± 5.29 × 10 2 pg/g, p < 0.01), and severe organ injury. Obviously, GPR120 facilitates IL-18 production and pathogen control via potassium efflux-dependent NOD-like receptor family pyrin domain-containing 3 (NLRP3) signaling. Mechanistically, GPR120 interaction with NLRP3 potentiates the NLRP3 inflammasome assembly. Thus, this study uncovers a novel role of GPR120 in host protection and reveals that GPR120 may be a potential therapeutic target for limiting pathogen infection.

STING-dependent trained immunity contributes to host defense against Clostridium perfringens infection via mTOR signaling

“…At present, only a few studies have demonstrated that toll-like receptor 4 accelerates granulopoiesis and enhances host defense against C. perfringens infection [ 21 ]. The toxins lecithinase and perfringolysin O of C. perfringens have been found to activate the NLRP3 inflammasome, and NLRP3 deficiency leads to increased host susceptibility to C. perfringens infection [ 22 , 23 ]. Consequently, the need for new preventive and therapeutic strategies has become more urgent.…”

Absent in Melanoma 2 Mediates Inflammasome Signaling Activation against Clostridium perfringens Infection

“…Previous studies have implied that inflammasome signaling emerges as an important aspect of host defense [ 11 , 22 ]. To investigate whether AIM2-mediated inflammasome signaling activation contributes to host protection against pathogenic C. perfringens invasion, Aim2 −/− mice were administrated with exogenous recombinant IL-18 (rIL−18) prior to pathogenic C. perfringens challenge, to confirm whether rIL-18 could rescue the defect in pathogenic C. perfringens control in the absence of Aim2 .…”

“…PRRs that have been characterized include cytosolic DNA sensors, RIG-I-like receptors, NOD-like receptors, Toll-like receptors, and C-type lectin receptors [ 9 ]. Previously, we have provided evidence that MLKL-NLRP3-extracellular traps and GPR120-NLRP3 signaling axes protect against C. perfringens infection by enhancing bactericidal activity [ 10 , 11 ]. Also, Toll-like receptor 4 signaling contributes to host defense against C. perfringens infection through replenishment of neutrophils and elimination of bacteria [ 12 ].…”

Clostridium perfringens phospholipase C, an archetypal bacterial virulence factor, induces the formation of extracellular traps by human neutrophils

“…C. perfringens induces NETs formation in murine neutrophils, which requires the intracellular pore-forming Mixed lineage kinase-like protein that oligomerizes in the membrane ( Liu et al., 2023a ; Liu et al., 2023b ). However, neither the signaling pathway involved in NET induction nor the C. perfringens virulence factor responsible for the NET inducing activity have been identified.…”