The NLRP3 inflammasome is a critical platform for the activation of Caspase-1 and secretion of biologically active IL-1? and IL-18 in response to bacterial toxins, particulate matter and certain endogenous stimuli. In addition to its protective role in innate immunity, dysregulation of the inflammasome by missense NLRP3 mutations causes autoinflammatory disorders. 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. In addition to the classical pathway, NLRP3 is activated by the noncanonical inflammasome in response to intracellular lipopolysaccharyde (LPS). Activation of the noncanonical inflammasome leads to Caspase-11-dependent pyroptosis, a proinflammatory form of cell death, which is critical for induction of endotoxic shock in mice. 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 NLRP3 activation. Another major gap is the events downstream of Caspase-11 responsible for pyroptosis in the noncanonical inflammasome pathway and the mechanism by which Caspase-11 activates the NLRP3 inflammasome. We have identified several factors that are required for the activation of NLRP3 and pyroptosis induced by the canonical and noncanonical inflammasomes. In this renewal application, we propose three specific Aims to understand the mechanism of NLRP3 activation and the events downstream of Caspase-11 that regulate pyroptosis and NLRP3 activation. Understanding how NLRP3 is activated and the components of the noncanonical inflammasome pathway required for pyroptosis is expected to provide critical insight into the role of the inflammasomes in host defense against pathogens and bacterial sepsis as well as the development of new therapeutic approaches to prevent and/or treat inflammasome-associated diseases.

Public Health Relevance

NLRP3 is a critical component of the innate immune system that forms the inflammasome, a molecular platform mediating Caspase-1 activation and secretion of biologically active IL-1? and IL-18. In addition to its protective role in innate immunity, dysregulation of the inflammasome by missense NLRP3 mutations causes autoinflammatory disorders and has been implicated in the pathogenesis of several acquired inflammatory disorders including gouty arthritis, silicosis, atherosclerosis, diabetes and Alzheimer's disease. Another important innate immune pathway is that induced by the noncanonical inflammasome. However, the mechanism of NLRP3 activation and the noncanonical inflammasome pathway remain poorly understood. In this grant application, we propose studies to understand the mechanism of NLRP3 activation via the classical and the noncanonical inflammasome.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AI063331-13
Application #
9391601
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Davidson, Wendy F
Project Start
2005-05-01
Project End
2020-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
13
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Pathology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Conos, Stephanie A; Chen, Kaiwen W; De Nardo, Dominic et al. (2017) Active MLKL triggers the NLRP3 inflammasome in a cell-intrinsic manner. Proc Natl Acad Sci U S A 114:E961-E969
He, Yuan; Zeng, Melody Y; Yang, Dahai et al. (2016) NEK7 is an essential mediator of NLRP3 activation downstream of potassium efflux. Nature 530:354-7
He, Yuan; Hara, Hideki; Núñez, Gabriel (2016) Mechanism and Regulation of NLRP3 Inflammasome Activation. Trends Biochem Sci 41:1012-1021
Bronner, Denise N; Abuaita, Basel H; Chen, Xiaoyun et al. (2015) Endoplasmic Reticulum Stress Activates the Inflammasome via NLRP3- and Caspase-2-Driven Mitochondrial Damage. Immunity 43:451-62
Symington, J W; Wang, C; Twentyman, J et al. (2015) ATG16L1 deficiency in macrophages drives clearance of uropathogenic E. coli in an IL-1?-dependent manner. Mucosal Immunol 8:1388-99
Yang, Dahai; He, Yuan; Muñoz-Planillo, Raul et al. (2015) Caspase-11 Requires the Pannexin-1 Channel and the Purinergic P2X7 Pore to Mediate Pyroptosis and Endotoxic Shock. Immunity 43:923-32
Shaw, Michael H; Kamada, Nobuhiko; Warner, Neil et al. (2011) The ever-expanding function of NOD2: autophagy, viral recognition, and T cell activation. Trends Immunol 32:73-9
Reimer, Thornik; Shaw, Michael H; Franchi, Luigi et al. (2010) Experimental cerebral malaria progresses independently of the Nlrp3 inflammasome. Eur J Immunol 40:764-9
Franchi, Luigi; Muñoz-Planillo, Raul; Reimer, Thornik et al. (2010) Inflammasomes as microbial sensors. Eur J Immunol 40:611-5
Toma, Claudia; Higa, Naomi; Koizumi, Yukiko et al. (2010) Pathogenic Vibrio activate NLRP3 inflammasome via cytotoxins and TLR/nucleotide-binding oligomerization domain-mediated NF-kappa B signaling. J Immunol 184:5287-97

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