NLRP12 negatively regulates proinflammatory cytokine production and host defense against Brucella abortus

Abstract

Brucella abortus is the causative agent of brucellosis, which causes abortion in domestic animals and undulant fever in humans. This bacterium infects and proliferates mainly in macrophages and dendritic cells where is recognized by pattern recognition receptors (PRRs) including Nod-like receptors (NLRs). Our group recently demonstrated the role of AIM2 and NLRP3 in Brucella recognition. Here, we investigated the participation of NLRP12 in innate immune response to B. abortus. We found that NLRP12 inhibits the early production of IL-12 in bone marrow-derived macrophages upon B. abortus infection. We also observed that NLRP12 suppresses in vitro NF-κB and MAPK signaling in response to Brucella. Moreover, we showed that NLRP12 modulates caspase-1 activation and IL-1β secretion in B. abortus infected-macrophages. Furthermore, we observed that mice lacking NLRP12 were more resistant in the early stages of B. abortus infection. NLRP12−/− infected-mice presented reduced bacterial burdens in the spleens and increased production of IFN-γ and IL-1β compared to wild-type controls. In addition, NLRP12 deficiency leads to reduction in granuloma number and size in mouse livers. Altogether, our findings suggest that NLRP12 plays an important role in regulating negatively the early inflammatory responses against B. abortus.

The Dual Immunoregulatory function of Nlrp12 in T Cell-Mediated Immune Response: Lessons from Experimental Autoimmune Encephalomyelitis

“…The results of this study and previous publications suggest that Nlrp12 inhibits NF-κB and MAPK signaling pathways in activated T cells [ 20 , 36 ]. The transcription of IL-2 gene is regulated by NF-κB, MAPK and Ca 2+ /calmodulin-dependent pathways [ 37 , 38 ].…”

“…The bifunctional nature of Nlrp12 has been previously reported in several studies [ 16 , 19 , 20 , 31 , 36 , 41 , 42 ]. Early in vitro studies suggest that Nlrp12 is an inflammatory NLR that interacts with ASC to form inflammasome [ 43 ].…”

The microbiome and cytosolic innate immune receptors

“…However, the immunosuppressive functions of Nlrp12 may be exploited by pathogens. Nlrp12‐dependent suppression of host immune responses facilitates the infection and persistence of invasive agents, including Salmonella Typhimurium , 111 Brucella abortus , 112 and vesicular stomatitis virus 113 …”

Canonical and noncanonical inflammasomes in intestinal epithelial cells

“…Yet more recent in vitro studies demonstrate that NLRP12 in fact dampens NF‐κB signalling (Arthur, Lich, Aziz, Kotb, & Ting, ; Lich et al, ; Williams et al, ). Likewise, in vivo, NLRP12 has also been shown to negatively regulates NF‐κB signalling in response to a variety of stimuli including chemical models of colitis and high‐fat diet (HFD) induced obesity (Allen et al, ; L. Chen et al, ; Truax et al, ; Zaki et al, ) as well as during Salmonella typhimurium and Brucella abortus infection (Silveira et al, ; Zaki, Man, Vogel, Lamkanfi, & Kanneganti, ) but not during Klebsiella pneumonia or Mycobacterium tuberculosis infection or in response to stimulation with purified lipopolysaccharide (LPS; Allen et al, ). However, the role of other inflammasomes components in these latter studies remains unclear, and further studies are needed to examine whether regulation of NF‐κB by NLRP12 represent an inflammasome‐dependent or inflammasome‐independent function of the protein.…”