Cryopyrin/NLRP3 Signaling in Inflammation and Innate Immunity

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Principal Investigator: Gabriel  Nunez
Organization: UNIVERSITY OF MICHIGAN AT ANN ARBOR
Fiscal Year: 2024
Award: $390,000
Funding agency: National Institute of Allergy and Infectious Diseases

The NLRP3 inflammasome is a critical platform for the activation of caspase-1 and secretion of biologically
active IL-1β and IL-18 in response to bacterial toxins, particulate matter and certain endogenous stimuli.
Furthermore, aberrant activation of NLRP3 has been linked to the pathogenesis of several acquired
inflammatory disorders including gouty arthritis, silicosis, atherosclerosis, diabetes and Alzheimer’s
disease. Although much progress has been made about the stimuli and cellular events that activate the
NLRP3 inflammasome, a major gap in the field is the identification of molecules that are required for
NLRP3 activation and the mechanism of caspase-1 activation in response to NLRP3 activating stimuli. The
Nek7 kinase was identified during the last cycle of the grant as a critical factor required for NLRP3
activation in response to a wide array of stimuli in vitro and in vivo. Nek7 was shown to act downstream of
K+ efflux to activate NLRP3. However, the mechanism by which K+ efflux activates NLRP3 via Nek7
remains unknown. Furthermore, the molecular events by which NLRP3 activates caspase-1 via the adaptor
ASC to induce ASC oligomerization and ASC speck formation are poorly understood. In this renewal
application, we propose studies in three specific Aims to (i) determine how K+ efflux activates the NLRP3
inflammasome through the kinase Nek7 using biochemical and in vivo approaches; (ii) identify factors that
regulate the phosphorylation of Nek7 to mediate the activation of NLRP3 and (iii) further characterize the
role of actin-based motor proteins in the mechanism of ASC-mediated inflammasome activation.
Understanding how NLRP3 is activated is expected to provide critical insight into the role of the
inflammasomes in different biological systems which will aid the development of new therapeutic
approaches to prevent and/or treat inflammasome-associated diseases.

Terms: <AD dementia><Actins><Alzheimer Type Dementia><Alzheimer disease dementia><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Disease><Alzheimers Dementia><Apoptosis-Related Cysteine Protease Caspase 1><Atherosclerosis><Atherosclerotic Cardiovascular Disease><Bacterial Toxins><Beta Proprotein Interleukin 1><Biochemical><CASP-1><CASP1><CASP1 gene><Caspase-1><Caspase-1 Gene><Cell Communication and Signaling><Cell Signaling><Development><Diabetes Mellitus><Disease><Disorder><Event><Gouty Arthritis><Grant><ICE Protease><IFN-Gamma-Inducing Factor Gene><IFN-gamma-Inducing Factor><IGIF><IGIF Gene><IL-1 Gamma><IL-1 Gamma Gene><IL-1 beta><IL-1 beta Convertase><IL-1 beta-Converting Enzyme><IL-1 β><IL-1-b><IL-18><IL-18 Gene><IL-1BC><IL-1b Converting Enzyme><IL-1g><IL-1g Gene><IL-1β><IL1-Beta><IL1-β><IL18><IL18 Protein><IL18 gene><IL1B Protein><IL1B-Convertase><IL1BC><IL1BCE><IL1F2><IL1F4><IL1F4 Gene><IL1β><In Vitro><Inflammasome><Inflammation><Inflammatory><Innate Immunity><Interferon-Gamma-Inducing Factor Gene><Interferon-gamma-Inducing Factor><Interleukin 1-B Converting Enzyme><Interleukin 1-Beta Convertase><Interleukin 18 (Interferon-Gamma-Inducing Factor)><Interleukin 18 (Interferon-Gamma-Inducing Factor) Gene><Interleukin 18 Proprotein><Interleukin 18 Proprotein Gene><Interleukin 1beta><Interleukin-1 Beta Converting Enzyme><Interleukin-1 Converting Enzyme><Interleukin-1 Gamma><Interleukin-1 Gamma Gene><Interleukin-1 beta><Interleukin-18><Interleukin-18 Precursor><Interleukin-18 Precursor Gene><Interleukin-1β><Intracellular Communication and Signaling><Kinases><Link><MGC12320><MGC12320 Gene><Mediating><Molecular><Motor><Native Immunity><Natural Immunity><Non-Specific Immunity><Nonspecific Immunity><Particulate Matter><Pathogenesis><Phosphorylation><Phosphotransferase Gene><Phosphotransferases><Preinterleukin 1 Beta><Primary Senile Degenerative Dementia><Protein Phosphorylation><Proteins><Role><Signal Transduction><Signal Transduction Systems><Signaling><Silicosis><Stimulus><Transphosphorylases><atheromatosis><atherosclerotic disease><atherosclerotic vascular disease><biological signal transduction><biological systems><developmental><diabetes><in vivo><insight><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><prevent><preventing><primary degenerative dementia><response><senile dementia of the Alzheimer type><social role>