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

## TL;DR

This study shows that loss of IGFBP2 in alveolar epithelial type 2 cells contributes to inflammation in severe COVID-19, suggesting IGFBP2 could be a potential treatment target.

## Contribution

The study identifies a novel role for IGFBP2 in reducing inflammation in alveolar epithelial type 2 cells during severe COVID-19.

## Key findings

- IGFBP2 mRNA is significantly downregulated in alveolar epithelial type 2 cells from patients with COVID-19 ARDS.
- Lentiviral expression of Igfbp2 reduces proinflammatory cytokines in mouse lung epithelial cells exposed to SARS-CoV-2 spike protein.
- Higher levels of TNF-α and IL-6 are found in alveolar epithelial type 2 cells from COVID-19 ARDS patients compared to other groups.

## 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.

The online version contains supplementary material available at 10.1186/s12931-025-03187-9.