Abstract
Keratin 8 (K8) is the main intestinal epithelial intermediate filament protein with proposed roles for colonic epithelial cell integrity. Here, we used mice lacking K8 in intestinal epithelial cells (floxed K8 and Villin-Cre1000 and Villin-CreERt2) to investigate the cell-specific roles of intestinal epithelial K8 for colonocyte function and pathologies. Intestinal epithelial K8 deletion decreased K8 partner proteins, K18–K20, 75–95%, and the remaining keratin filaments were located at the colonocyte apical regions with type II K7, which decreased 30%. 2-Deoxy-2-[18F]-fluoroglucose positron emission tomography in vivo imaging identified a metabolic phenotype in the lower gut of the conditional K8 knockouts. These mice developed intestinal barrier leakiness, mild diarrhea, and epithelial damage, especially in the proximal colon. Mice exhibited shifted differentiation from enterocytes to goblet cells, displayed longer crypts and an increased number of Ki67 + transit-amplifying cells in the colon. Significant proproliferative and regenerative signaling occurred in the IL-22, STAT3, and pRb pathways, with minor effects on inflammatory parameters, which, however, increased in aging mice. Importantly, colonocyte K8 deletion induced a dramatically increased sensitivity to azoxymethane-induced tumorigenesis. In conclusion, intestinal epithelial K8 plays a significant role in colonocyte epithelial integrity maintenance, proliferation regulation and tumor suppression.Graphical abstract
Highlights
The constant renewal of the epithelial cell layer in the intestinal mucosa ensures the maintenance of the barrier between the lumen and the submucosa
Keratin immunostainings confirmed the complete loss of Keratin 8 (K8) in the K 8flox/ flox; Villin-Cre colonic epithelium (Supplemental Fig. 3A), and a significant decrease of K7, K18 and K19 throughout the crypt with remaining staining in the apical compartment of colonic epithelial cells (Supplemental Fig. 3A, B)
We demonstrate the importance of the main colonocyte intermediate filament K8 for colon health in vivo, utilizing mouse models where the main colonic epithelial type II keratin K8 was deleted from intestinal epithelial cells
Summary
The constant renewal of the epithelial cell layer in the intestinal mucosa ensures the maintenance of the barrier between the lumen and the submucosa. In simple type epithelia, such as the liver and intestine, the main members of the type I K18-K23 and type II K7-K8 simple epithelial keratin (SEK) family are expressed in a tissue type and differentiation-specific manner [2]. In both the small and large intestine, K8 is the major and probably the most important type II keratin [2], while K19 is its most abundant type I partner together with lower levels of K18 and K20 [3]. SEK protein levels are dynamically regulated during intestinal stress conditions [5]
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