Activated Clec4n < sup > hi < /sup > Neutrophils Aggravate Lung Injury in an Endothelial IGFBP7 Dependent Manner

Am J Respir Cell Mol Biol. 2024 Apr 4. doi: 10.1165/rcmb.2024-0017OC. Online ahead of print.ABSTRACTThe role of endothelial cells in Acute lung injury (ALI) has been widely elaborated, but little is known about the role of different subtypes of endothelial cells in ALI. ALI models were established by lipopolysaccharide. Single-cell RNA sequencing was used to identify differential molecules in endothelial subtypes and heterogeneity of lung immune cells. Specific antibodies were used to block IGFBP7 protein, and AAVshIGP7 was used to specifically knock down IGFBP7. Here, we found that Insulin-like growth factor binding protein 7 (IGFBP7) was the most differentially expressed molecule in diverse subsets of endothelial cells and that IGFBP7 was strongly associated with inflammatory responses. Elevated IGFBP7 significantly exacerbated barrier dysfunction in ALI, whereas blockade of IGFBP7 partially reversed barrier damage. General capillary cells (gCap) are the primary source of elevated serum IGFBP7 after ALI. Using single-cell RNA sequencing, we identified significantly increased Clec4nhi neutrophils in ALI mice, whereas IGFBP7 knockdown significantly reduced infiltration of Clec4nhi cells and mitigated barrier dysfunction in ALI. In addition, we found that IGFBP7 activated the NFκB signaling axis by promoting phosphorylation and ubiquitination degradation of F-box/WD repeat-containing protein 2 (FBXW2), thereby exacerbating barrier dysfunction in ALI. Taken together, our data ...
Source: Mol Biol Cell - Category: Molecular Biology Authors: Source Type: research