p120-Catenin Expressed in Alveolar Type II Cells Is Essential for the Regulation of Lung Innate Immune Response

Abstract

The integrity of the lung alveolar epithelial barrier is required for the gas exchange and is important for immune regulation. Alveolar epithelial barrier is composed of flat type I cells, which make up approximately 95% of the gas-exchange surface, and cuboidal type II cells, which secrete surfactants and modulate lung immunity. p120-catenin (p120; gene symbol CTNND1) is an important component of adherens junctions of epithelial cells; however, its function in lung alveolar epithelial barrier has not been addressed in genetic models. Here, we created an inducible type II cell-specific p120-knockout mouse (p120EKO). The mutant lungs showed chronic inflammation, and the alveolar epithelial barrier was leaky to (125)I-albumin tracer compared to wild type. The mutant lungs also demonstrated marked infiltration of inflammatory cells and activation of NF-κB. Intracellular adhesion molecule 1, Toll-like receptor 4, and macrophage inflammatory protein 2 were all up-regulated. p120EKO lungs showed increased expression of the surfactant proteins Sp-B, Sp-C, and Sp-D, and displayed severe inflammation after pneumonia caused by Pseudomonas aeruginosa compared with wild type. In p120-deficient type II cell monolayers, we observed reduced transepithelial resistance compared to control, consistent with formation of defective adherens junctions. Thus, although type II cells constitute only 5% of the alveolar surface area, p120 expressed in these cells plays a critical role in regulating the innate immunity of the entire lung.

Integrated Omics Analysis of Pathogenic Host Responses during Pandemic H1N1 Influenza Virus Infection: The Crucial Role of Lipid Metabolism

“…The protein network was enriched for hematological system development and function, glycolysis, and cellular oxidative stress processes (Table S4). We also found proteins related to innate immune and antiviral responses including Trim25, Stat1, Mx1, as well as p120-catenin (encoded by CTNND1 gene) known to protect alveolar epithelial barrier integrity (Chignalia et al, 2015). In relation to lipid metabolism, protein module p2 contained apolipoproteins, Apoh and Apoa4, and gene module g5 contained fatty acid metabolism genes, FABP3 and SCD , as well as PTGER3 , encoding a receptor of PGE 2 known to inhibit alveolar macrophage type I interferon responses during influenza virus infection (Coulombe et al, 2014) (Table S5).…”

Dlk1-Mediated Temporal Regulation of Notch Signaling Is Required for Differentiation of Alveolar Type II to Type I Cells during Repair

“…Next we determined, by qRT-PCR of whole-lung lysates obtained 3 days after PA injury, whether disrupting Dlk1 in AT2 affected the inflammatory response of mutant lungs. When examining several factors involved in inflammation (i.e., MIP2, MCP, interleukin-6 [IL-6], tumor necrosis factor alpha [TNF-α], and ICAM-1; Chignalia et al, 2015 ), we found no significant difference between WT and mutant mice ( Figure S4 ).…”

p120 Catenin Suppresses Basal Epithelial Cell Extrusion in Invasive Pancreatic Neoplasia

“…In contrast, targeted knockout of p120 catenin in murine salivary gland (21), intestine (31,41), brain (42), mammary gland (43), kidney (36), eye (44), epidermis (31,45), and lung (46) is not sufficient to promote formation of cancer. It is therefore likely that the requirement for p120 catenin in development and progression of cancer is tissue-specific.…”