Processing of angiocrine alarmin IL-1α in endothelial cells promotes lung and liver fibrosis

Chunxue Zhang, Jie Ma, Xu Zhang, Dengcheng Zhou, Zhongwei Cao, Lina Qiao, Guo Chen, Liming Yang, Bi Sen Ding

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Fibrosis results from excessive scar formation after tissue injury. Injured cells release alarmins such as interleukin 1 (IL-1) α and β as primary mediators initiating tissue repair. However, how alarmins from different cell types differentially regulate fibrosis remains to be explored. Methods: Here, we used tissue specific knockout strategy to illustrate a unique contribution of endothelial cell-derived IL-1α to lung and liver fibrosis. The two fibrotic animal model triggered by bleomycin and CCl4 were used to study the effects of endothelial paracrine/angiocrine IL-1α in fibrotic progression. Human umbilical vein endothelial cells (HUVEC) were performed to explore the production of angiocrine IL-1α at both transcriptional and post-transcriptional levels in vitro. Results: We found that endothelial paracrine/angiocrine IL-1α primarily promotes lung and liver fibrosis during the early phase of organ repair. By contrast, myeloid cell-specific ablation of IL-1α in mice resulted in little influence on fibrosis, suggesting the specific pro-fibrotic role of IL-1α from endothelial cell but not macrophage. In vitro study revealed a coordinated regulation of IL-1α production in human primary endothelial cells at both transcriptional and post-transcriptional levels. Specifically, the transcription of IL-1α is regulated by RIPK1, and after caspase-8 (CASP8) cleaves the precursor form of IL-1α, its secretion is triggered by ion channel Pannexin 1 upon CASP8 cleavage. Conclusions: Endothelial cell-produced IL-1α plays a unique role in promoting organ fibrosis. Furthermore, the release of this angiocrine alarmin relies on a unique molecular mechanism involving RIPK1, CASP8, and ion channel Pannexin 1.

Original languageEnglish
Article number112176
JournalInternational Immunopharmacology
Volume134
DOIs
StatePublished - 15 Jun 2024
Externally publishedYes

Keywords

  • Fibrosis
  • IL-1α
  • angiocrine alarmin
  • endothelial cell
  • tissue injury

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