Hedgehog-induced ZFYVE21 promotes chronic vascular inflammation by activating NLRP3 inflammasomes in T cells

The zinc finger protein ZFYVE21 is involved in immune signaling. Using humanized mouse models, primary human cells, and patient samples, we identified a T cell-autonomous role for ZFYVE21 in promoting chronic vascular inflammation associated with allograft vasculopathy. Ischemia-reperfusion injury (...

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Bibliographic Details
Published in:	Science signaling Vol. 16; no. 777; p. eabo3406
Main Authors:	Jiang, Bo, Wang, Shaoxun, Song, Guiyu, Jiang, Quan, Fan, Matthew, Fang, Caodi, Li, Xue, Soh, Chien Lin, Manes, Thomas D, Cheru, Nardos, Qin, Lingfeng, Ren, Pengwei, Jortner, Bianca, Wang, Qianxun, Quaranta, Emma, Yoo, Peter, Geirsson, Arnar, Davis, Robert P, Tellides, George, Pober, Jordan S, Jane-Wit, Dan
Format:	Journal Article
Language:	English
Published:	United States 21-03-2023
Subjects:	Animals Endothelial Cells - metabolism Hedgehog Proteins - genetics Hedgehog Proteins - metabolism Humans Inflammasomes - genetics Inflammasomes - metabolism Inflammation - genetics Inflammation - metabolism Intracellular Signaling Peptides and Proteins - metabolism Membrane Proteins - metabolism Mice Mice, Inbred C57BL NLR Family, Pyrin Domain-Containing 3 Protein - genetics NLR Family, Pyrin Domain-Containing 3 Protein - metabolism T-Lymphocytes - metabolism
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Summary:	The zinc finger protein ZFYVE21 is involved in immune signaling. Using humanized mouse models, primary human cells, and patient samples, we identified a T cell-autonomous role for ZFYVE21 in promoting chronic vascular inflammation associated with allograft vasculopathy. Ischemia-reperfusion injury (IRI) stimulated endothelial cells to produce Hedgehog (Hh) ligands, which in turn induced the production of ZFYVE21 in a population of T memory cells with high amounts of the Hh receptor PTCH1 (PTCH cells, CD3 CD4 CD45RO PTCH1 PD-1 ), vigorous recruitment to injured endothelia, and increased effector responses in vivo. After priming by interferon-γ (IFN-γ), Hh-induced ZFYVE21 activated NLRP3 inflammasome activity in T cells, which potentiated IFN-γ responses. Hh-induced NLRP3 inflammasomes and T cell-specific ZFYVE21 augmented the vascular sequelae of chronic inflammation in mice engrafted with human endothelial cells or coronary arteries that had been subjected to IRI before engraftment. Moreover, the population of PTCH T cells producing high amounts of ZFYVE21 was expanded in patients with renal transplant-associated IRI, and sera from these patients expanded this population in control T cells in a manner that depended on Hh signaling. We conclude that Hh-induced ZFYVE21 activates NLRP3 inflammasomes in T cells, thereby promoting chronic inflammation.
ISSN:	1937-9145
DOI:	10.1126/scisignal.abo3406