Innate Immune Function of the Adherens Junction Protein p120-Catenin in Endothelial Response to Endotoxin

Abstract

Sepsis-induced acute lung injury is a common clinical disorder in critically ill patients that is associated with high mortality. In this study, we investigated the role of p120-catenin (p120), a constituent of endothelial adherens junctions, in regulating the innate immune function of lungs. In mice in which acute lung injury was induced by i.p. administration of LPS, we observed a rapid decrease in the expression of p120 in lungs. The p120 protein expression was correlated inversely with severity of inflammation. Suppression of p120 expression in lung endothelial cells in mice using small interfering RNA resulted in high sensitivity to endotoxin and greatly increased the mortality compared with controls. Knockdown of p120 also increased the expression of ICAM-1, neutrophil recruitment, production of cytokines TNF-α and IL-6, pulmonary transvascular protein permeability, and lung water content in response to LPS. We demonstrated that endothelial p120 modulates lung innate immune function by interfering with the association of TLR4 with its adaptor MyD88 to block TLR4 signaling and NF-κB activation in endothelial cells. In conclusion, these studies have uncovered a novel innate immune function of endothelial p120 in downregulating the lung inflammatory response to endotoxin through the suppression of TLR4 signaling.

Reactive Oxygen Species in Inflammation and Tissue Injury

“…Liu et al (248) showed that LPS/TLR4 signaling activated Src family kinases by enhancing the interaction of TRAF6 with cSrc and Fyn and promoting transendothelial albumin flux. In another study, Wang et al (442) reported a direct role of p120-catenin in the regulation of LPSmediated increase in endothelial permeability. They showed that the inhibition of p120-catenin expression in endothelial cells increased MyD88 and TLR4 association, ICAM-1 expression and enhanced the severity of LPSinduced lung inflammation.…”

Inhibition of endotoxin-induced airway epithelial cell injury by a novel family of pyrrol derivates

“…Second, we did not use primary alveolar epithelial cells; however, there is a plethora of published studies validating the use of human BEAS-2B and A549 cells as an acceptable model of epithelial cell injury and for studying the LPS-induced effects in the airway epithelium. [11][12][13][14][15][16]25,[28][29][30][31][32][33][34][35] Third, further studies are needed to elucidate whether there are other mechanisms by which the pyrrol compound DTA0118 elicits its anti-inflammatory and antiapoptotic activities. Fourth, TLR4, Ikβα, and β-actin were not adjusted for the cell number.…”

“…2 Epithelial cells generate cytokines, chemokines, and antimicrobial peptides in response to inflammatory stimuli, 25,26 and airway epithelium controls lung inflammation and injury through NF-κB. 27 Numerous experimental studies have used human A549 alveolar and BEAS-2B bronchial epithelial cell lines to examine the acute lung inflammatory response induced by LPS, as an acceptable, validated, and suitable in vitro airway epithelial injury model based on the initial steps of the development of sepsis and ARDS [11][12][13][14][15][16]25,[28][29][30] and continue being extensively used. [31][32][33][34][35] We selected E. coli LPS because it has been used in most endotoxin-induced lung injury models 36,37 and LPS is a key pathogen recognition molecule for sepsis 27 that induces apoptosis in lung cells.…”

Epigenetic modifiers reduce inflammation and modulate macrophage phenotype during endotoxemia-induced acute lung injury

“…Macrophages, endothelial cells and neutrophils are crucial in regulating inflammation as well as lung vascular endothelial cell integrity in LPS-induced ALI (Di et al, 2012;Wang et al, 2011). We chose to study the macrophages because of their role in orchestrating inflammation (Kochanek et al, 2012;Song et al, 2001).…”