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<p>The coronavirus disease 2019 (COVID-19) global pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, our understanding of SARS-CoV-2-induced inflammation in alveolar epithelial cells remains very limited. The contributions of intracellular insulin-like growth factor binding protein-2 (IGFBP2) to SARS-CoV-2 pathogenesis are also unclear. In this study, we have uncovered a critical role for IGFBP2, specifically in alveolar epithelial&#xa0;type&#xa0;2 cells (AEC2), in the immunopathogenesis of COVID-19. Using bulk RNA sequencing, we show that <i>IGFBP2</i> mRNA expression is significantly downregulated in primary AEC2 cells isolated from fibrotic lung regions from patients with COVID-19-acute respiratory distress syndrome (ARDS) compared to those with idiopathic pulmonary fibrosis (IPF) alone or IPF with a history of COVID-19. Using multicolor immunohistochemistry, we demonstrated that IGFBP2 and its selective ligands IGF1 and IGF2 were significantly reduced in AEC2 cells from patients with COVID-ARDS, IPF alone, or IPF with COVID history than in those from age-matched donor controls. Further, we demonstrated that lentiviral expression of <i>Igfbp2</i> significantly reduced mRNA expression of proinflammatory cytokines—Tnf-α, Il1β, Il6, Stat3, Stat6 and chemokine receptors—Ccr2 and Ccr5—in mouse lung epithelial cells challenged with SARS-CoV-2 spike protein injury (S2; 500&#xa0;ng/mL). Finally, we demonstrated higher levels of cytokines—TNF-α; IL-6 and chemokine receptor—CCR5 in AEC2 cells from COVID-ARDS patients compared to the IPF alone and the IPF with COVID history patients. Altogether, these data suggest that anti-inflammatory properties of IGFBP2 in AEC2 cells and its localized delivery may serve as potential therapeutic strategy for patients with COVID-19.</p> Graphical Abstract <p></p>

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Alveolar epithelial type 2 cell specific loss of IGFBP2 activates inflammation in COVID-19

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月22日

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  • Valentina Pujadas,
  • Chiahsuan Chin,
  • Narendra V. Sankpal,
  • James Buhrmaster,
  • Ashwini Arjuna,
  • Rajat Walia,
  • Michael A. Smith,
  • Oliver Eickelberg,
  • Ross M. Bremner,
  • Thalachallour Mohanakumar,
  • Angara Sureshbabu

摘要

The coronavirus disease 2019 (COVID-19) global pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, our understanding of SARS-CoV-2-induced inflammation in alveolar epithelial cells remains very limited. The contributions of intracellular insulin-like growth factor binding protein-2 (IGFBP2) to SARS-CoV-2 pathogenesis are also unclear. In this study, we have uncovered a critical role for IGFBP2, specifically in alveolar epithelial type 2 cells (AEC2), in the immunopathogenesis of COVID-19. Using bulk RNA sequencing, we show that IGFBP2 mRNA expression is significantly downregulated in primary AEC2 cells isolated from fibrotic lung regions from patients with COVID-19-acute respiratory distress syndrome (ARDS) compared to those with idiopathic pulmonary fibrosis (IPF) alone or IPF with a history of COVID-19. Using multicolor immunohistochemistry, we demonstrated that IGFBP2 and its selective ligands IGF1 and IGF2 were significantly reduced in AEC2 cells from patients with COVID-ARDS, IPF alone, or IPF with COVID history than in those from age-matched donor controls. Further, we demonstrated that lentiviral expression of Igfbp2 significantly reduced mRNA expression of proinflammatory cytokines—Tnf-α, Il1β, Il6, Stat3, Stat6 and chemokine receptors—Ccr2 and Ccr5—in mouse lung epithelial cells challenged with SARS-CoV-2 spike protein injury (S2; 500 ng/mL). Finally, we demonstrated higher levels of cytokines—TNF-α; IL-6 and chemokine receptor—CCR5 in AEC2 cells from COVID-ARDS patients compared to the IPF alone and the IPF with COVID history patients. Altogether, these data suggest that anti-inflammatory properties of IGFBP2 in AEC2 cells and its localized delivery may serve as potential therapeutic strategy for patients with COVID-19.

Graphical Abstract