Airway epithelial integrin β4‐deficiency exacerbates lipopolysaccharide‐induced acute lung injury

Abstract

Airway epithelial cells, the first barrier of the respiratory tract, play an indispensable role in innate immunity. Integrin β4 (ITGB4) is a structural adhesion molecule that is involved in the pathological progression of acute inflammatory diseases and is downregulated in asthmatic patients. Research has shown that endothelial ITGB4 has proinflammatory properties in acute lung injury (ALI). However, the role of epithelial ITGB4 in a murine ALI model is still unknown. This study investigated the role of ITGB4 in lipopolysaccharide (LPS)-induced ALI. We found that ITGB4 in the airway epithelium had remarkably increased after the introduction of LPS in vivo and in vitro. Then, we constructed airway epithelial cell-specific ITGB4 knockout (ITGB4 −/− ) mice to study its role in ALI. At a time point of 12 h after the tracheal injection of LPS, ITGB4 −/− mice showed increased macrophages (mainly M1-type macrophages) and neutrophil infiltration into the lungs; inflammation-related proteins including interleukin (IL)-6, tumor necrosis factor, and IL-17A were significantly elevated compared to their levels in ITGB4 +/+ mice. Furthermore, we investigated the role of ITGB4 in the anti-inflammatory response. Intriguingly, in the ITGB4 −/− + LPS group, we found significantly reduced expression of antiinflammatory factors, including IL-10 messenger RNA (mRNA) and ARG-1 mRNA.We also observed that monocyte chemotactic protein (MCP-1) increased significantly both in vivo and in vitro. Airway epithelium activates macrophages, most likely driven by MCP-1, which we confirmed in the coculture of epithelia and macrophages. These phenomena indicate that ITGB4 in airway epithelial cells plays an important role in the process of inflammation and activation of macrophages in ALI. Overall, these data demonstrated a novel link between airway epithelial ITGB4 and the inflammatory response in LPS-induced ALI.

Conditional knockout of ITGB4 in bronchial epithelial cells directs bronchopulmonary dysplasia

“…It has been reported that deleting β1 integrin in lung epithelium beginning at E10.5 results in abnormal lung development with a 100% fatality rate at the age of 16 weeks 12 . Based on our observation, knockout of ITGB4 in airway epithelial cells did not affect the overall survival rate; besides, in our previous research, we observed that after LPS treatment, the mRNA expression of anti‐inflammatory factors, including IL‐10 and ARGA‐1, was significantly reduced in the lung tissue of β4 ccsp.cre mice compared with wild‐type mice 48 . Under the stimulation of HDM, it is more likely for β4 ccsp.cre mice to acquire airway hyper‐responsiveness and asthma than wild‐type mice 39 .…”

“… 12 Based on our observation, knockout of ITGB4 in airway epithelial cells did not affect the overall survival rate; besides, in our previous research, we observed that after LPS treatment, the mRNA expression of anti‐inflammatory factors, including IL‐10 and ARGA‐1, was significantly reduced in the lung tissue of β4 ccsp.cre mice compared with wild‐type mice. 48 Under the stimulation of HDM, it is more likely for β4 ccsp.cre mice to acquire airway hyper‐responsiveness and asthma than wild‐type mice. 39 These results suggest a different role of β4 than β1 in lung development.…”

PDGF Promotes Dermal Fibroblast Activation via a Novel Mechanism Mediated by Signaling Through MCHR1

“…Genes and biological processes involved in fibrosis were exclusively enriched by PDGF-BB in NHDF. For example, PDGF-BB decreased ITGB4 expression, a signature that is associated with enhanced lipopolysaccharide-induced inflammation ( 38 ). GRPR is the G protein-coupled receptor that binds to gastrin-releasing peptide (GRP).…”

“…We identified 1,473 DE genes that are unique to ["PDGF-BB vs VC" in siCtr NHDF] and thus considered to be driven by PDGF-BB through MCHR1 (Supplementary Table 6). Gastrin releasing peptide receptor (GRPR) (log2FC = 4.843; q = 0.00689), integrin subunit beta (ITGB) 4 (log2FC = -5.015; q = 0.00014), and vitronectin (VTN) (log2FC = -4.901; q = 0.00029) were in the list of DE genes (Supplementary Table 6), all genes reported to be associated with fibrosis or inflammation (37)(38)(39).…”

MMP12 is a Potential Predictive and Prognostic Biomarker of Various Cancers Including Lung Adenocarcinoma

“… 37 Overexpressed MMP12 mRNA may promote the progression and metastasis of ESCA, LIHC, and LUSC and is associated with a poor prognosis in cancer patients. 25 , 38 , 39 Additionally, a high expression of MMP12 mRNA in LUAD promotes lymph node metastasis. 12 Similarly, our study detected that MMP12 is differently expressed in various cancers and that MMP12 is associated with patients’ cancer status and prognosis in several cancers.…”