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

  • Int Immunopharmacol. 2024 Jun 15:134:112176. doi: 10.1016/j.intimp.2024.112176.
Chunxue Zhang  1 ,  Jie Ma  1 ,  Xu Zhang  2 ,  Dengcheng Zhou  1 ,  Zhongwei Cao  1 ,  Lina Qiao  3 ,  Guo Chen  4 ,  Liming Yang  5 ,  Bi-Sen Ding  6
Affiliations
  • 1. Key Laboratory of Birth Defects of MOE, State Key Laboratory of Biotherapy, West China Second Hospital, College of Life Sciences, Sichuan University, Chengdu 610041, China.
  • 2. Department of Pathophysiology, Harbin Medical University, Harbin 150081, China.
  • 3. Key Laboratory of Birth Defects of MOE, State Key Laboratory of Biotherapy, West China Second Hospital, College of Life Sciences, Sichuan University, Chengdu 610041, China. Electronic address: [email protected].
  • 4. Department of Anesthesiology, The Research Units of West China（2018RU012）-Chinese Academy of Medical Sciences, West China Hospital, Sichuan University, China. Electronic address: [email protected].
  • 5. Department of Pathophysiology, Harbin Medical University, Harbin 150081, China. Electronic address: [email protected].
  • 6. Key Laboratory of Birth Defects of MOE, State Key Laboratory of Biotherapy, West China Second Hospital, College of Life Sciences, Sichuan University, Chengdu 610041, China. Electronic address: [email protected].
PMID: 38723369 DOI: 10.1016/j.intimp.2024.112176
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.

Keywords
Fibrosis; IL-1α; angiocrine alarmin; endothelial cell; tissue injury.
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