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Activation of the NLRP3 Inflammasome by Dopamine Is Regulated by Dual GSDMD and GSDMB Cleavage Pathways Associated with Mitochondrial Dysregulation

Award Number: F31AI203627
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 07/28/2026
PERIOD OF PERFORMANCE END DATE: 07/27/2028

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Activation of the NLRP3 Inflammasome by Dopamine Is Regulated by Dual GSDMD and GSDMB Cleavage Pathways Associated with Mitochondrial Dysregulation - PROJECT SUMMARY/ABSTRACT Inflammasomes are innate immune signaling hubs that coordinate inflammatory cytokine release and pyroptotic cell death. Aberrant inflammasome activity is implicated in a broad spectrum of chronic inflammatory conditions, yet the pathways by which different physiological signals regulate inflammasome responses remain insufficiently defined. Our recent findings reveal that the dopamine (DA), classically studied as a neurotransmitter, directly primes the activation of a novel NLRP3 inflammasome activation pathway in human monocyte-derived macrophages (hMDMs). In the presence of an inflammasome activation trigger (BzATP), DA induces parallel cleavage of Gasdermin D (GSDMD) and Gasdermin B (GSDMB). This dual gasdermin response uniquely induced by DA – it was not recapitulated by any pathogen-recognition receptor (PRR) agonist tested. Notably, while GSDMD is processed through caspase-mediated activity, the GSDMB cleavage pathway mediated by DA depends on granzyme-B activity, suggesting a novel, endogenous protease pathway in human macrophages. Because GSDMB is absent in rodents, this DA–GSDMB axis potentially represents a human- specific inflammatory mechanism that has not been identified in murine systems and may underlie previously described species-specific differences in dopaminergic immune responses. While the specific trigger for DA-mediated GSDMB cleavage is not clear, our data show that DA disrupts mitochondrial homeostasis and induces glycolytic shift, which has been shown to initiate inflammasome activity. Specifically, DA treatment induces excessive mitochondrial fission driven by DRP-1 phosphorylation, elevated mitochondrial superoxide (MitoSOX), and release of oxidized mitochondrial DNA (mtDNA). These alterations temporally coincide with inflammasome activation, and inhibiting these effects by blocking DRP-1 mediated fission suppresses DA-induced inflammasome assembly and cytokine maturation. This supports our premise that DA regulates NLRP3 inflammasome activation via two mechanistically distinct but parallel pathways targeting GSDMDNT and GSDMBNT, which are directly linked to mitochondrial dysregulation. To address this, Aim 1 will identify the specific proteases responsible for GSDMB and GSDMD cleavage, determine their contributions to IL-1β secretion and pyroptosis, and define the subcellular localization of the cleaved GSDM fragments. Aim 2 will define how DA disrupts mitochondrial dynamics and metabolism to promote inflammasome assembly, using complementary pharmacologic and genetic approaches, and will map these mitochondrial effects to discrete stages of inflammasome activation. Clarifying how DA engages gasdermin-dependent and mitochondrial signaling will establish a novel human-specific inflammatory pathway and reveal mechanistic links between dopaminergic signaling, mitochondrial stress, and innate immune activation in inflammatory disease and therapeutic contexts.


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: 2026 ( Subtotal = $50,114 )
2026	2026	DREXEL UNIVERSITY	3141 CHESTNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	1	7/28/2026	NEW	$50,114
2026	2026	DREXEL UNIVERSITY	3141 CHESTNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	001	1	7/28/2026	NEW	$0
														Subtotal = $50,114

Grand Total All Awards = $50,114

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Activation of the NLRP3 Inflammasome by Dopamine Is Regulated by Dual GSDMD and GSDMB Cleavage Pathways Associated with Mitochondrial Dysregulation

Award Number: F31AI203627

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 07/28/2026

PERIOD OF PERFORMANCE END DATE: 07/27/2028

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