All multicellular organisms have developed the ability to mount an innate immune response to invading microbes, and this system provides the first line of defense against these agents. In addition, differences in the innate response triggered by different pathogens provide essential early information to the organism concerning the nature of the threat at hand, thus ensuring proper tailoring of the adaptive immune response to efficiently eliminate the infectious agent. Cells of the immune system detect pathogen-associated molecular patterns, or PAMPs, expressed by the microbes, and this in turn leads to dramatic changes in gene expression and cell function, changes which together act to initiate a coordinated protective response to the pathogen. Exposure of macrophages to a broad spectrum of PAMPs results in increased production and release of cytokines, notably the processing and release of the pleiotropic, pro-inflammatory cytokine, IL-1b. Maturation and release of IL-1b is dependent on the assembly of cytoplasmic protein complexes referred to as """"""""inflammasomes"""""""". The inflammasome is composed of an NLR protein that oligomerizes in response to changes in the cell triggered either directly or indirectly by the encountered PAMPs or DAMPs (pathogen or danger-associated molecular patterns). The oligomerized NLR proteins recruit additional proteins to the complex via their CARD and PYRIN domains, including ASC (PYCARD), and pro-caspase-1. The recruitment of two pro-caspase-1 proteins leads to autocatalysis and release of active enzyme, which is then available for cleavage of pro IL-1b into its biologically active form. The NLRP proteins have emerged as critical regulators of the activity of the inflammasome and thus of the innate immune response in mammals. The most extensively studied of these is NLRP3. This protein is mutated in individuals suffering from familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS) and chronic infantile neurological cutaneous articular syndrome/neonatal-onset multisystem inflammatory diseases (CINCA/NOMID). Individuals heterozygous for missense mutations in this gene suffer from excessive inflammation characterized by increased serum IL-1b. More recently, common variants in the NLRP3 locus have been associated with an increasing number of chronic diseases including Crohn's disease and arthritis. In this application we propose a novel approach for study of the molecular pathophysiology of CAPS and for defining the functionality of disease associated polymorphisms in this gene.
The NLRP proteins have emerged as critical regulators of the activity of the inflammasome and thus of the innate immune response in mammals. The most extensively studied of these is NLRP3. This protein is mutated in individuals suffering from familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS) and chronic infantile neurological cutaneous articular syndrome/neonatal-onset multisystem inflammatory diseases (CINCA/NOMID). Individuals heterozygous for missense mutations in this gene suffer from excessive inflammation characterized by increased serum IL-1b. More recently, common variants in the NLRP3 locus have been associated with an increasing number of chronic diseases including Crohn's disease and arthritis. In this application we propose a novel approach for study of the molecular pathophysiology of CAPS and for defining the functionality of disease associated polymorphisms in this gene.
| Perkins, Darren J; Richard, Katharina; Hansen, Anne-Marie et al. (2018) Autocrine-paracrine prostaglandin E2 signaling restricts TLR4 internalization and TRIF signaling. Nat Immunol 19:1309-1318 |
| Hagar, Jon A; Edin, Matthew L; Lih, Fred B et al. (2017) Lipopolysaccharide Potentiates Insulin-Driven Hypoglycemic Shock. J Immunol 199:3634-3643 |
| Abdul-Sater, Ali A; Tattoli, Ivan; Jin, Lei et al. (2013) Cyclic-di-GMP and cyclic-di-AMP activate the NLRP3 inflammasome. EMBO Rep 14:900-6 |
