Requirement of epithelial integrin-linked kinase for facilitation of Citrobacter rodentium-induced colitis

Abstract

BackgroundIntegrin-linked kinase (ILK) is a serine-threonine kinase that transduces extracellular matrix-related cues into intracellular signals, with fundamental roles in cell motility, development and cancer. Recently ILK been shown to have an important role in bacterial epithelial cell attachment, through ILK-bacterial OspE binding. Here we report on the role of epithelial derived ILK in response to Citrobacter rodentium infection.MethodsC. rodentium was administered to both control and intestinal epithelial cell ILK knockout mice. Histological inflammatory scores were assessed, and cytokines measured by ELISA as well as RT-PCR, in mouse colons. Bacterial colonization was determined by plating homogenates onto MacConkey agar, and immunofluorescence microscopy performed using anti-LPS and anti-Tir antibodies.ResultsILK-ko mice exhibited reduced weight loss at 15 days post-infection (p < 0.01) and demonstrated reduced histological inflammatory scores (p < 0.01), reduced CCL2 and pro-inflammatory cytokines. This was not due to reduced colonization, but was associated with an altered pattern of C. rodentium bacterial migration. Attenuated fibronectin expression was found in the ILK-ko mice. C. rodentium exposure was shown to increase ILK expression in cell lines, and in murine epithelium in vivo. In ILK-ko mice reduced activation of ser473Akt and reduced crypt proliferation, together with reduced cyclin D1 expression were observed.ConclusionsILK influences the host response to C. rodentium -induced infection, independently of reduced colonization in the ILK knockout mice. The reduced inflammation and dramatically attenuated hyperplastic cryptal response to infection in this group, are at least in part the result of, the reduction in CCL2 and cyclin D1 expression respectively.

CXCL9 Contributes to Antimicrobial Protection of the Gut during Citrobacter rodentium Infection Independent of Chemokine-Receptor Signaling

“…A correlation between invasion of C . rodentium into crypts and increased host pathology has been observed in other studies [ 43 , 44 ] and so protecting this niche against intestinal pathogens is a key function for the innate immune system.…”

Role of integrin-linked kinase in drug resistance of lung cancer

“…ILK, an important serine/threonine protein phosphatase, plays a key role in the regulation of signal transduction and the remodeling of the tumor ECM. 11 High expression of ILK was closely related to the occurrence and development of gastrointestinal, breast, and lung tumors. 12 – 15 A study by Chen et al showed that ILK could promote the process of lung cancer EMT, and silencing of ILK gene could significantly inhibit the invasion and metastasis of lung cancer.…”

A complex interplay between the extracellular matrix and the innate immune response to microbial pathogens

“…Systems biology approaches elucidating the ECM interactome network regulated by Trypanosoma cruzi and its gp83 ligand, which mediates trypanosome attachment and entry, have shown that activation of gp83 receptors in the cell via extracellular signal‐regulated kinase 1/2 results in up‐regulation of laminin γ 1 and thrombospondin expression to facilitate trypomastigote recruitment, enhancing cellular infection . In mice, Citrobacter rodentium infection induces osteopontin and fibronectin expression through integrin‐linked kinase activation, facilitating bacterial colonization of the intestine . High expression levels of osteopontin have also been shown to be induced in murine acute and chronic coxsackievirus B3‐myocarditis together with those of MMP‐3, TIMP1, urokinase‐type plasminogen activator and TGF‐ β 1 and, in turn, procollagen‐1 α mRNA expression and fibrosis.…”