Salmonella exploits NLRP12-dependent innate immune signaling to suppress host defenses during infection

Abstract

The nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain containing 12 (NLRP12) plays a protective role in intestinal inflammation and carcinogenesis, but the physiological function of this NLR during microbial infection is largely unexplored. Salmonella enterica serovar Typhimurium (S. typhimurium) is a leading cause of food poisoning worldwide. Here, we show that NLRP12-deficient mice were highly resistant to S. typhimurium infection. Salmonella-infected macrophages induced NLRP12-dependent inhibition of NF-κB and ERK activation by suppressing phosphorylation of IκBα and ERK. NLRP12-mediated downregulation of proinflammatory and antimicrobial molecules prevented efficient clearance of bacterial burden, highlighting a role for NLRP12 as a negative regulator of innate immune signaling during salmonellosis. These results underscore a signaling pathway defined by NLRP12-mediated dampening of host immune defenses that could be exploited by S. typhimurium to persist and survive in the host.

NOD-Like Receptors: Guardians of Intestinal Mucosal Barriers

“…However, recent work of Zaki et al identified a contrary role of NLRP12 in S. Tm infections. Here, NLRP12-deficient mice were hyperresistant to S. Tm, and NLRP12 was identified as a suppressor of S. Tm-induced proinflammatory reactions (116). In line with this observation, NLRP12 was also reported as a suppressor of gastrointestinal inflammation upon DSS treatment and of tumorgenesis in an AOM/DSS cancer model by negative regulation of NF-B and AKT signaling (2,117).…”

A mutualistic symbiosis between a parasitic mite and a pathogenic virus undermines honey bee immunity and health

“…This result indicates that DWV infection could have a negative effect on NF-κB activation by enhancing the transcription of its negative modulator Amel\LRR. The possibility that DWV adopts a virulence strategy somewhat similar to that recently described for Salmonella, which targets an NLR protein that negatively regulates NF-κB signaling (31), is an intriguing hypothesis meriting further research efforts.…”

Beyond the inflammasome: regulatory NOD-like receptor modulation of the host immune response following virus exposure

“…NLRP12 functions as a negative regulator of inflammation by modulating elements of the NF-k B signalling pathway ( Fig. 3) (Allen et al, 2012a, b;Arthur et al, 2007;Lei et al, 2012Lei et al, , 2013Moore et al, 2008;Tsuchiya et al, 2010;Wagner et al, 2009;Xia et al, 2011;Zaki et al, 2014). This hypothesis is supported by recent in vivo studies utilizing Nlrp12 2/2 mice in models of acute colitis and colitis-associated tumorigenesis.…”