Keratin-8-deficient mice develop chronic spontaneous Th2 colitis amenable to antibiotic treatment

Abstract

Keratin 8 (K8) is the major intermediate filament protein present in intestinal epithelia. Depending on the mouse genetic background, absence of K8 causes embryonic lethality or colonic hyperplasia and colitis. We studied disease progression, the inflammatory responses, and role of luminal bacteria in K8-null mice in order to characterize the intestinal pathology of K8-associated colitis. Colon lymphocytes were isolated for analysis of their phenotype and cytokine production, and vascular and lymphocyte adhesion molecule expression in K8–/– mice of varying ages. K8–/– mice had a marked increase in TCRβ-positive/CD4-positive T cells infiltrating the colon lamina propria, in association with enhanced Th2 cytokine (IL-4, IL-5 and IL-13) production. K8–/– mice show early signs of inflammation even prior to weaning, that increases with age, and their epithelial cells overexpress MHC class II antigens. The chronic colitis is related to increased CD4-positive infiltrating T cells displaying memory and naive phenotypes, and an altered vascular endothelium with aberrant expression of peripheral node addressin. Analysis of normal gut-specific homing molecules, reveals an increased number of α4β7-positive cells and vascular mucosal addressin cell adhesion molecule-1 in K8-null colons. Antibiotic treatment markedly decreased colon inflammation and ion transporter AE1/2 mistargeting, indicating that luminal bacteria play an important role in the observed phenotype. Therefore, K8-null mice develop chronic spontaneous Th2-type colitis due to a primary epithelial rather than immune cell defect, which is amenable to antibiotic therapy. These mice provide a model to investigate epithelial-leukocyte and epithelial-microbial cross-talk.

Preventive Effects of Spirogyra neglecta and a Polysaccharide Extract against Dextran Sodium Sulfate Induced Colitis in Mice

“…Here we observed down-regulation of both KRT8 and KRT18 in mouse colonic mucosa induced by DSS, perhaps as a reflexion of severe damage to the epithelium. Several studies have indicated that KRT8-null mice suffer chronic inflammation (Baribault et al, 1994;Habtezion et al, 2005). Thus, mutation of KRT8 in humans also leads to epithelial instability in the gut and may play a role in IBD (Owens et al, 2004).…”

Absence of keratin 8 confers a paradoxical microflora-dependent resistance to apoptosis in the colon

“…It is difficult to study the relationship of microflora to the colonic hyperplasia in the absence of inflammation, because treatment with antibiotics reverses both the inflammatory response and the colonic hyperplasia in K8 −/− mice (11). To assess whether inflammation per se or inflammation triggered by microbes contributes to the observed alteration in apoptosis, we examined the differences in colonocyte apoptosis in another chronic colitis model, namely the TCRα −/− model of chronic colitis (31 −/− and K8 +/+ colonocyte genes following antibiotic treatment.…”

“…−/− mice develop colonic hyperplasia and chronic spontaneous colitis (9,10) that is amenable to early treatment with broad-spectrum antibiotics (11).…”

Cytokeratins of the Liver and Intestine Epithelial Cells During Development and Disease

“…When the surviving mice were further backcrossed onto an FVB background, it resulted in generation of mice with 50% embryo lethality. Although the surviving mice had a normal life span, they exhibited an ulcerative colitis-like phenotype (Baribault, Penner et al 1994;Toivola, Krishnan et al 2004;Habtezion, Toivola et al 2005) and considerable hepatocyte fragility and susceptibility to liver injury (Loranger, Duclos et al 1997). Although both CK8-and CK18-deficient mice lack hepatocyte keratin filaments, their phenotype is partially different.…”