NLRP12 in autoimmune diseases

Nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) are a group of cytoplasmic sensors that survey danger signals released by invading pathogen or damaged self-tissues. NLRs can be categorized into subgroups based on their ability to form inflammasome, potentiate inflammatory signaling, act as transcriptional regulators and negatively regulate inflammatory pathways. NLRP12, first described about 10 years ago, is a cytoplasmic sensor to be categorized as a negative regulator of inflammation. A recent study has also shown that NLRP12 can form an inflammasome during infection with Yersinia pestis, although this study needs to be substantiated by independent groups [1]. Two seminal studies in 2011 showed that NLRP12 is a crucial negative regulator of NF-κB signaling pathway [2, 3]. The absence of NLRP12 in mice resulted in severe uncontrolled inflammation that rendered these NLRP12-deficient mice highly susceptible to experimental colitis and inflammation-induced tumorigenesis [2, 3]. NLRP12 was crucial in both hematopoietic and non-hematopoietic compartment for controlling overt inflammation, colitis and colitis-associated tumorigenesis. We have further shown that NLRP12 also negatively regulates NF-κB signaling during Salmonella infection to limit inflammation [4]. While the etiology of infectious diseases, colitis and cancer require coordination of several immune and stromal cells, most of the mechanistic insights on the molecular underpinnings of NLRP12 have only been conducted in innate immune cells that include macrophages and dendritic cells. Specifically, T cells are central to the regulation of all of these disease manifestations but the role of NLRP12 in T cells was not known. Analysis of NLRP12 expression in various cell populations revealed that T cells express relatively higher levels of NLRP12 in comparison to both dendritic cells and macrophages [5]. While NLRP12 was not required for negative and positive selection of T cells in the thymus, our studies showed that Nlrp12-/-T cells produce higher levels of Th1 (IFN-γ), Th2 (IL-4) and Th17 (IL-17) cytokines following ex vivo stimulation, suggesting a cell intrinsic role for NLRP12 in negatively regulating T cell activation [5]. In agreement, in a T cell transfer-induced colitis model, mice receiving Nlrp12-/-T cells exhibited dramatically severe colitis when compared to mice receiving WT T cells. In addition to severe colitis, mice receiving Nlrp12-/-T cells also displayed severe inflammation of the skin and ears, i.e. atopic dermatitis. Further analysis of cytokines in these diseased mice showed that the disease transferring Nlrp12-/-T cells also produced excessive levels of Th2 cytokines such as IL-4, IL-5 and IL-13, which are critical in …