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Published on: December 26, 2012
Alveolar epithelial type 2 cell specific loss of IGFBP2 activates inflammation in COVID-19
Valentina Pujadas1,2, Chiahsuan Chin1,2, Narendra V Sankpal1,2
1Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, 124 W. Thomas Road, Ste. 100, Phoenix, AZ, 85013, USA.
Abstract:
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.
Insights
This study reveals insulin-like growth factor binding protein-2 (IGFBP2) is crucial in alveolar epithelial cells for COVID-19 pathogenesis. Lower IGFBP2 levels correlate with severe COVID-19, suggesting IGFBP2
Area of Science:
- Pulmonary immunology and pathology
- Molecular mechanisms of viral pathogenesis
- Cellular and molecular medicine
Background:
- Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19, leading to significant inflammation in alveolar epithelial cells.
- The role of intracellular insulin-like growth factor binding protein-2 (IGFBP2) in SARS-CoV-2 pathogenesis is not well understood.
- Alveolar epithelial type 2 (AEC2) cells are critical in lung injury and repair, and their response to SARS-CoV-2 is key to understanding COVID-19.
Purpose of the Study:
- To investigate the role of IGFBP2 in AEC2 cells during COVID-19 immunopathogenesis.
- To determine the expression levels of IGFBP2 and its ligands in lung tissues from COVID-19 patients.
- To explore the potential of IGFBP2 as a therapeutic target for COVID-19-related lung inflammation.
Main Methods:
- Bulk RNA sequencing was used to analyze IGFBP2 mRNA expression in primary AEC2 cells from patients with COVID-19-associated acute respiratory distress syndrome (ARDS) and idiopathic pulmonary fibrosis (IPF).
- Multicolor immunohistochemistry was employed to assess IGFBP2, IGF1, and IGF2 protein levels in AEC2 cells.
- Lentiviral expression of Igfbp2 was used in mouse lung epithelial cells challenged with SARS-CoV-2 spike protein to evaluate its effect on inflammatory markers.
Main Results:
- IGFBP2 mRNA was significantly downregulated in AEC2 cells from COVID-ARDS patients compared to IPF patients.
- IGFBP2, IGF1, and IGF2 protein levels were reduced in AEC2 cells from patients with COVID-ARDS, IPF alone, or IPF with COVID history compared to controls.
- Lentiviral Igfbp2 expression reduced pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) and chemokine receptors (CCR2, CCR5) in mouse lung cells exposed to SARS-CoV-2 spike protein.
Conclusions:
- IGFBP2 plays a critical role in regulating inflammation within AEC2 cells during COVID-19.
- Reduced IGFBP2 levels in AEC2 cells are associated with increased pro-inflammatory responses in COVID-19.
- Therapeutic strategies involving localized delivery of IGFBP2 may offer a potential treatment for COVID-19-induced lung inflammation.
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