1. Academic Validation
  2. Disruption of pulmonary microvascular endothelial barrier by dysregulated claudin-8 and claudin-4: uncovered mechanisms in porcine reproductive and respiratory syndrome virus infection

Disruption of pulmonary microvascular endothelial barrier by dysregulated claudin-8 and claudin-4: uncovered mechanisms in porcine reproductive and respiratory syndrome virus infection

  • Cell Mol Life Sci. 2024 May 28;81(1):240. doi: 10.1007/s00018-024-05282-4.
Weifeng Sun 1 2 3 Weixin Wu 1 2 Xinyu Fang 1 2 Xinna Ge 1 2 Yongning Zhang 1 2 Jun Han 1 2 Xin Guo 1 2 Lei Zhou 4 5 Hanchun Yang 6 7
Affiliations

Affiliations

  • 1 National Key Laboratory of Veterinary Public Health Safety, College of Veterinary Medicine, China Agricultural University, Beijing, 100193, People's Republic of China.
  • 2 Key Laboratory of Animal Epidemiology of Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, China Agricultural University, Beijing, 100193, People's Republic of China.
  • 3 China Institute of Veterinary Drug Control, Beijing, 100081, People's Republic of China.
  • 4 National Key Laboratory of Veterinary Public Health Safety, College of Veterinary Medicine, China Agricultural University, Beijing, 100193, People's Republic of China. Leosj@cau.edu.cn.
  • 5 Key Laboratory of Animal Epidemiology of Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, China Agricultural University, Beijing, 100193, People's Republic of China. Leosj@cau.edu.cn.
  • 6 National Key Laboratory of Veterinary Public Health Safety, College of Veterinary Medicine, China Agricultural University, Beijing, 100193, People's Republic of China. yanghanchun1@cau.edu.cn.
  • 7 Key Laboratory of Animal Epidemiology of Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, China Agricultural University, Beijing, 100193, People's Republic of China. yanghanchun1@cau.edu.cn.
Abstract

The pulmonary endothelium is a dynamic and metabolically active monolayer of endothelial cells. Dysfunction of the pulmonary endothelial barrier plays a crucial role in the acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), frequently observed in the context of viral pneumonia. Dysregulation of tight junction proteins can lead to the disruption of the endothelial barrier and subsequent leakage. Here, the highly pathogenic porcine reproductive and respiratory syndrome virus (HP-PRRSV) served as an ideal model for studying ALI and ARDS. The alveolar lavage fluid of pigs infected with HP-PRRSV, and the supernatant of HP-PRRSV infected pulmonary alveolar macrophages were respectively collected to treat the pulmonary microvascular endothelial cells (PMVECs) in Transwell culture system to explore the mechanism of pulmonary microvascular endothelial barrier leakage caused by viral Infection. Cytokine screening, addition and blocking experiments revealed that proinflammatory cytokines IL-1β and TNF-α, secreted by HP-PRRSV-infected macrophages, disrupt the pulmonary microvascular endothelial barrier by downregulating claudin-8 and upregulating claudin-4 synergistically. Additionally, three transcription factors interleukin enhancer binding factor 2 (ILF2), general transcription factor III C subunit 2 (GTF3C2), and thyroid hormone receptor-associated protein 3 (THRAP3), were identified to accumulate in the nucleus of PMVECs, regulating the transcription of claudin-8 and claudin-4. Meanwhile, the upregulation of ssc-miR-185 was found to suppress claudin-8 expression via post-transcriptional inhibition. This study not only reveals the molecular mechanisms by which HP-PRRSV Infection causes endothelial barrier leakage in acute lung injury, but also provides novel insights into the function and regulation of tight junctions in vascular homeostasis.

Keywords

miR-185; Acute lung injury (ALI); Claudin-4 (CLDN4); Claudin-8 (CLDN8); Porcine reproductive and respiratory syndrome virus (PRRSV); Pulmonary microvascular endothelial barrier.

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