Sunday, November 24, 2024 11/24/2024

Autophagic regulation of inflammasome-mediated hyperactive state in living macrophages

Award Number: R21AR079766
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Abstract Nucleotide-binding domain (NBD) and leucine-rich repeat (LRR)-containing proteins (NLRs) assemble into functional supramolecular organizing centers called the inflammasomes, which serve as an interface of host defense against pathogens or other types of danger. Canonical inflammasomes activate caspase-1, an inflammatory protease that upon activation, triggers two important biological responses: 1) processing of cytokine interleukin-1b (IL-1b), and 2) formation of plasma membrane gasdermin D pores to potentiate inflammatory cell death (pyroptosis). Cytokine secretion and pyroptosis are coupled under a steady-state condition, as the GSDMD pores on the plasma membrane, which permeates IL-1b, can also compromise the cell membrane integrity leading to the lytic cell death. Interestingly, in a hyperactive state following inflammasome activation, cells show sustained cytokine secretion but retain viability, even though this process is dependent on GSDMD pores formed on the plasma membrane. The underlying mechanisms which recalibrate GSDMD to only sustain the release of the interleukin, but not pyroptosis, are poorly understood. Autophagy is regarded as an important regulator of inflammation. In our recent studies, we found that inflammasomes are regulated by an aggresome-like mechanism that promotes inflammasome assembly (Yang) but also induces autophagy to dampen caspase-1 processing and IL-b secretion (Yin) (Magupalli et al., Science, 2020). Our studies are consistent with previous reports showing that mice lacking the key autophagic gene, Atg16L1, in hematopoietic cells, were highly susceptible to dextran sulphate sodium-induced acute colitis, with the secretion of a high amount of IL-1b and IL-18 cytokines. In addition, these inflammatory phenotypes were alleviated by injection of anti-IL-1b and IL-18 antibodies in mice. Collectively, our and other published results demonstrate that autophagy directly regulates the extent to which inflammasomes activate downstream signals. However, it is unclear if autophagy can regulate the switch between a hyperactive state and a pyroptotic state of macrophages. In this application, we will investigate the potential link between autophagy and macrophage hyperactivation using inflammasome assays and cellular imaging.


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: 2024 ( Subtotal = $0 )
2024	2022	NEW YORK BLOOD CENTER, INC	310 E 67TH ST	NEW YORK	NY	10065	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	3	11/8/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$176,100
2024	2022	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	11/8/2023	NON-COMPETING CONTINUATION	-$176,100
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $250,560 )
2023	2023	NEW YORK BLOOD CENTER, INC.	310 E 67TH ST	NEW YORK	NY	10065	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	3	2/9/2023	SUPPLEMENT FOR EXPANSION	$85,400
2023	2022	NEW YORK BLOOD CENTER, INC.	310 E 67TH ST	NEW YORK	NY	10065	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	3	2/3/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$165,160
2023	2022	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	2/2/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $250,560

Issue Date FY: 2022 ( Subtotal = $192,753 )
2022	2022	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	6/29/2022	NON-COMPETING CONTINUATION	$192,753
														Subtotal = $192,753

Issue Date FY: 2021 ( Subtotal = $233,640 )
2021	2021	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	7/12/2021	NEW	$233,640
														Subtotal = $233,640

Grand Total All Awards = $676,953

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Autophagic regulation of inflammasome-mediated hyperactive state in living macrophages

Award Number: R21AR079766

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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