Damage-induced pyroptosis drives endog thymic regeneration via induction of Foxn1 by purinergic receptor activation.

Autor:	Kinsella S; Program in Immunology, Division of Translational Science and Therapeutics, Fred Hutchinson Cancer Center, Seattle WA, 98109, US.; Immunotherapy Integrated Research Center, Fred Hutchinson Cancer Research Center, Seattle WA, 98109, US., Evandy CA; Program in Immunology, Division of Translational Science and Therapeutics, Fred Hutchinson Cancer Center, Seattle WA, 98109, US.; Immunotherapy Integrated Research Center, Fred Hutchinson Cancer Research Center, Seattle WA, 98109, US., Cooper K; Program in Immunology, Division of Translational Science and Therapeutics, Fred Hutchinson Cancer Center, Seattle WA, 98109, US.; Immunotherapy Integrated Research Center, Fred Hutchinson Cancer Research Center, Seattle WA, 98109, US., Cardinale A; Department of Pediatric Hematology and Oncology, Bambino Gesù Children's Hospital, IRCCS, Rome, 00146, Italy., Iovino L; Program in Immunology, Division of Translational Science and Therapeutics, Fred Hutchinson Cancer Center, Seattle WA, 98109, US.; Immunotherapy Integrated Research Center, Fred Hutchinson Cancer Research Center, Seattle WA, 98109, US., deRoos P; Program in Immunology, Division of Translational Science and Therapeutics, Fred Hutchinson Cancer Center, Seattle WA, 98109, US.; Immunotherapy Integrated Research Center, Fred Hutchinson Cancer Research Center, Seattle WA, 98109, US., Hopwo KS; Program in Immunology, Division of Translational Science and Therapeutics, Fred Hutchinson Cancer Center, Seattle WA, 98109, US.; Immunotherapy Integrated Research Center, Fred Hutchinson Cancer Research Center, Seattle WA, 98109, US., Smith CW; Program in Immunology, Division of Translational Science and Therapeutics, Fred Hutchinson Cancer Center, Seattle WA, 98109, US.; Immunotherapy Integrated Research Center, Fred Hutchinson Cancer Research Center, Seattle WA, 98109, US., Granadier D; Program in Immunology, Division of Translational Science and Therapeutics, Fred Hutchinson Cancer Center, Seattle WA, 98109, US.; Immunotherapy Integrated Research Center, Fred Hutchinson Cancer Research Center, Seattle WA, 98109, US.; Medical Scientist Training Program, University of Washington, Seattle WA, 98195, US., Sullivan LB; Human Biology Division, Fred Hutchinson Cancer Center, Seattle WA, 98109, US., Velardi E; Department of Pediatric Hematology and Oncology, Bambino Gesù Children's Hospital, IRCCS, Rome, 00146, Italy., Dudakov JA; Program in Immunology, Division of Translational Science and Therapeutics, Fred Hutchinson Cancer Center, Seattle WA, 98109, US.; Immunotherapy Integrated Research Center, Fred Hutchinson Cancer Research Center, Seattle WA, 98109, US.; Department of Immunology, University of Washington, Seattle WA, 98195, US.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2023 Jan 20. Date of Electronic Publication: 2023 Jan 20.
DOI:	10.1101/2023.01.19.524800
Abstrakt:	Endogenous thymic regeneration is a crucial process that allows for the renewal of immune competence following stress, infection or cytoreductive conditioning. Fully understanding the molecular mechanisms driving regeneration will uncover therapeutic targets to enhance regeneration. We previously demonstrated that high levels of homeostatic apoptosis suppress regeneration and that a reduction in the presence of damage-induced apoptotic thymocytes facilitates regeneration. Here we identified that cell-specific metabolic remodeling after ionizing radiation steers thymocytes towards mitochondrial-driven pyroptotic cell death. We further identified that a key damage-associated molecular pattern (DAMP), ATP, stimulates the cell surface purinergic receptor P2Y2 on cortical thymic epithelial cells (cTECs) acutely after damage, enhancing expression of Foxn1 , the critical thymic transcription factor. Targeting the P2Y2 receptor with the agonist UTPγS promotes rapid regeneration of the thymus in vivo following acute damage. Together these data demonstrate that intrinsic metabolic regulation of pyruvate processing is a critical process driving thymus repair and identifies the P2Y2 receptor as a novel molecular therapeutic target to enhance thymus regeneration. Competing Interests: CONFLICT OF INTEREST J.A.D., S.K., and L.I., have submitted a patent application pending around these findings to promote thymus regeneration.
Databáze:	MEDLINE
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