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Density dependent immune activation in human epithelial cells

ABSTRACT: Mucosal tissues, such as the intestinal and airway epithelium, function as semipermeable barriers essential for maintaining immune homeostasis. Type III interferons (IFNλs) are key regulators of antiviral defense and barrier integrity within these mucosal surfaces. While interferon signaling is traditionally associated with responses to pathogenic challenges, it has become evident that constitutive basal interferon signaling also occurs in pathogen-free environments. However, the mechanisms and functions of basal IFNλ signaling have not been elucidated yet. Our study revealed a novel mechanism and function of basal IFNλ signaling in epithelial cells. We demonstrated that the interplay between cell density and basal immune response. Basal signaling drives the expression of numerous ISGs, such as Mx1, IFIT1, and ISG15, which are absent in IFNλ2/3 KO and IFNLR KO cells. Beyond its antiviral function, we discovered that basal IFNλ2/3 signaling is critical for maintaining epithelial barrier integrity and polarization. Its absence disrupts cell polarity, barrier function, and integrity, leading to increased permeability. Collectively, our study establishes a critical and novel role for basal IFNλ2/3 signaling in maintaining epithelial barrier function and highlights the involvement of multiple pathways in regulating this signaling beyond its antiviral roles.

ORGANISM(S): Homo sapiens

PROVIDER: GSE279172 | GEO | 2025/06/02

REPOSITORIES: GEO

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Project description:The apical junctional complex (AJC), composed of tight junctions and adherens junctions, is essential for maintaining epithelial barrier function. Since cigarette smoking and chronic obstructive pulmonary disease (COPD), the major smoking-induced disease, are both associated with increased lung epithelial permeability, we hypothesized that smoking alters the transcriptional program regulating AJC integrity in the small airway epithelium (SAE), the primary site of pathological changes in COPD. Transcriptome analysis revealed a global down-regulation of physiological AJC gene expression in the SAE of healthy smokers (n=53) compared to healthy nonsmokers (n=59), an observation associated with changes in molecular pathways regulating epithelial differentiation such as PTEN signaling and accompanied by induction of cancer-related AJC genes. Genome-wide co-expression analysis identified a smoking-sensitive AJC transcriptional network. The overall expression of AJC-associated genes was further decreased in COPD smokers (n=23). Exposure of human airway epithelial cells to cigarette smoke extract in vitro resulted in down-regulation of several AJC-related genes, accompanied by decreased transepithelial resistance. Thus, cigarette smoking alters the AJC gene expression architecture in the human airway epithelium, providing a molecular basis for the dysregulation of airway epithelial barrier function during the development of smoking-induced lung disease. The apical junctional complex (AJC), composed of tight junctions and adherens junctions, is essential for maintaining epithelial barrier function. Since cigarette smoking and chronic obstructive pulmonary disease (COPD), the major smoking-induced disease, are both associated with increased lung epithelial permeability, we hypothesized that smoking alters the transcriptional program regulating AJC integrity in the small airway epithelium (SAE), the primary site of pathological changes in COPD. In this study, microarray analysis of the SAE obtained from 53 healthy nonsmokers, 59 healthy smokers, and 23 smokers with COPD was performed to determine physiological AJC gene expression architecture in the SAE and its modification by cigarette smoking and during the development of COPD.

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Density dependent immune activation in human epithelial cells

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