Chronic inflammatory syndromes arise as a consequence of genetic polymorphism in combination with environment, pathogens and diet. Colitis is a form of inflammatory bowel diseases (IBD) that is characterized by ulcers in the colon. IBD are commonly associated with the exaggerated production of inflammatory cytokines, which are regulated by the activation of various cell signaling pathways and the NF-kB family of transcription factors. The NLR (nucleotide binding domain and leucine-rich-repeat-containing or NOD-like receptor) family of proteins has received much attention in IBD research due to the genetic association of NOD2 with Crohns'disease. We found that NLRP12, a new NLR family member acts as a negative regulator of inflammation by suppressing NF-kB activation via multiple mechanisms, including the induction of proteasome mediated degradation of NIK (NF-kB inducing kinase). In addition to negative regulators of innate immunity, studies have shown that nuclear receptors (NRs) can suppress inflammation, tumor formation, and induce cell apoptosis. A greater understanding of how NLRP12 can interact with NRs is important in understanding the processes that are crucial in the maintenance of homeostasis and the reduction of inflammation in a healthy gut. We employed an in silico protein interactome analysis and found that NLRP12 can interact with NRs. In addition, we localized several potential NR regulatory elements in the promoter of NLRP12. The goal of this proposal is to determine the intersection of NRs with NLRP12 in regulating NF-kB activation in colon.
Normal cellular homeostasis requires a crosstalk between immune responses and metabolic regulation that is altered by the type of diet. NLRP12 is a novel intracellular innate immune sensor, and we and others showed that it functions as a negative regulator of NF-kB to reduce inflammation in the gut. I have found that nuclear receptors (NRs) that are immunosuppressive can induce NLRP12 expression. On the other hand, NLRP12 appear to enhance the function of such NRs. Thus we propose that the two synergize to maintain a homeostatic non-inflammatory state. A better understanding of the mechanisms by which NRs and NLRP12, intersect and contribute to the containment of colitis will provide better insights for the prevention and/or treatment of this disease. Thus this proposa has an important translational relevance.
