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A novel mechanism for NLRP3 inflammasome activation in human macrophages

Award Number: R01AI165797
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/16/2022
PERIOD OF PERFORMANCE END DATE: 05/31/2027

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A novel mechanism for NLRP3 inflammasome activation in human macrophages - Infections and cellular stress can trigger cytoplasmic pattern recognition receptors to assemble an inflammasome complex, which promotes the release of the inflammatory cytokines IL-1β, IL-18 and the induction of pyroptotic cell death. Inflammasome responses are also perpetuated and propagated to bystander cells. Ultimately, this response contributes to pathogen clearance and wound healing. However, excessive inflammasome activation can contribute to- or cause debilitating symptoms associated with inflammatory diseases. Particularly, the NLRP3 inflammasome has been directly linked to numerous diseases. It has a unique position by not only sensing infections, but also cellular stress and tissue damage. Even though the NLRP3 inflammasome is of utmost importance for balancing between homeostasis and disease, and is therefore a prime target for novel treatment strategies, the underlying molecular mechanisms, particularly in human macrophages, are still poorly understood. There are numerous human inflammasome components that are absent in mice and their functional contribution to human health and disease are even less well understood than the more conserved factors. Elucidating unique human responses is the main focus of our lab. Innate immune receptor oligomerization initiates inflammatory host responses, including inflammasome activation. The research outlined in this proposal is designed to mechanistically unravel a novel NLRP3 inflammasome activation concept in human macrophages. We discovered a novel NLRP3 inflammasome component in human macrophages, which interacts with NLRP3, but is absent from mice and our preliminary studies revealed that NLRP3 requires this co-sensor for oligomerization as well as for recruiting the inflammasome adaptor, ASC. Furthermore, NLRP3 and its co-sensor are necessary for efficiently nucleating ASC polymerization and caspase-1 activation. Knock out of the co-sensor phenocopies NLRP3 knock out in human macrophages. Significantly, it is absolutely necessary for cytokine release driven by NLRP3 mutations that cause Cryopyrin-Associated Periodic Syndrome (CAPS). We propose two specific aims that investigate the mechanism and function of the co-sensor in NLRP3 inflammasome assembly and activation in macrophages, as well as the molecular events that enable this co-sensor to promote NLRP3 inflammasome activation. We will utilize CRISPR/Cas9 knock out and restored expression of wild type and mutant co-sensor proteins and a humanized mouse expressing the human co-sensor for studying its function in vivo. We expect that our research will uncover novel molecular mechanisms that not only change our current understanding of control mechanisms that prevent inappropriate NLRP3 inflammasome activation for maintaining homeostasis and human health, but also NLRP3-driven pathologies in inflammatory diseases. The outcomes of our study will move the field forward and will be highly significant for understanding disease pathologies and for the development of novel therapies that benefit patients and positively affect human health.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $1,531,430 )
2025	2025	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Allergy and Infectious Diseases Research	001	4	6/9/2025	EXTENSION WITH OR WITHOUT FUNDS	$1,531,430
2025	2024	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	3	6/6/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $1,531,430

Issue Date FY: 2024 ( Subtotal = $765,715 )
2024	2024	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	3	5/22/2024	NON-COMPETING CONTINUATION	$765,715
														Subtotal = $765,715

Issue Date FY: 2023 ( Subtotal = $765,715 )
2023	2023	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	2	5/16/2023	NON-COMPETING CONTINUATION	$765,715
														Subtotal = $765,715

Issue Date FY: 2022 ( Subtotal = $765,715 )
2022	2022	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	LOS ANGELES	CA	90048	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	1	6/15/2022	NEW	$765,715
														Subtotal = $765,715

Grand Total All Awards = $3,828,575

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A novel mechanism for NLRP3 inflammasome activation in human macrophages

Award Number: R01AI165797

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 06/16/2022

PERIOD OF PERFORMANCE END DATE: 05/31/2027

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