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

Abstract

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 hi cells, CD3 + CD4 + CD45RO + PTCH1 hi PD-1 hi ), 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 hi 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.

A ZFYVE21-Rubicon-RNF34 signaling complex promotes endosome-associated inflammasome activity in endothelial cells

“…While induction of inflammasome proteins canonically occurs following PAMP-induced NF-κB, this process may be subsumed by endogenous molecules including reactive oxygen species, metabolites, and hypoxia during sterile inflammation associated with transplant rejection 38 . Various cytokines including IFN-γ, though dispensable for IL-1β production in human macrophages, may similarly prime NLRP3 inflammasomes 39 , a process that we found occurs following EC-mediated direct allorecognition in vitro and in various humanized mouse models including coronary artery xenografts 2 , 9 , 40 in vivo. While abundant IFN-γ is induced in our in vitro and in vivo approaches above, our studies do not rule out the contribution(s) from other endogenous molecules eliciting inflammasome priming.…”

Comprehensive analysis of necroptosis-related genes in renal ischemia-reperfusion injury

“…DGF is a common manifestation seen after renal transplantation and always occurs after severe IRI ( 30 ). Therefore, we aimed to develop a predictive model for DGF based on the NR-DEGs from the GSE43974 dataset.…”

Hedgehog costimulation during ischemia-reperfusion injury potentiates cytokine and homing responses of CD4+ T cells

“…CD4 + T cells, while lacking primary cilium, organelles mediating Hh signaling, highly express Hh pathway components, including Ptch, Smo, and Gli effectors, and are capable of both receipt and transmission of Hh inputs, possibly via signals derived from immune synapses ( 23 ). Hh signaling encodes programs for positive costimulation ( 24 , 25 ) to regulate type 1 ( 14 ), Th2 ( 26 ), Treg ( 27 ), and Th17 ( 28 ) effector polarization.…”

“…We previously explored this notion using a humanized mouse model incorporating IRI-treated human coronary artery xenografts ( 14 , 15 ). We found that soluble and surface-bound Hh ligands, including Sonic, Desert, and Indian Hedgehog, were upregulated by complement membrane attack complexes (MACs) during the reperfusion phase of IRI, and the same Hh ligands delivered costimulatory but not mitogenic signals to memory CD4 + CD45RO + T cells (Tmem), endowing these cells with heightened effector and migratory responses ( 14 ).…”

“…Hh signaling upregulates the expression of its own component signaling molecules ( 19 ), and exploiting this, we found that the observed functional alterations induced by Hh selectively occurred on Tmem highly expressing Ptch1, the surface receptor for Hh ligands. We found that surface levels of Ptch1, a marker for Hh costimulatory strength, were directly proportional to the ability of these cells to mediate chronic inflammation of IRI-treated human artery xenografts ( 14 ).…”