Abstract
The actin cytoskeleton is a critical regulator of intestinal mucosal barrier permeability, and the integrity of epithelial adherens junctions (AJ) and tight junctions (TJ). Non muscle myosin II (NM II) is a key cytoskeletal motor that controls actin filament architecture and dynamics. While NM II has been implicated in the regulation of epithelial junctions in vitro, little is known about its roles in the intestinal mucosa in vivo. In this study, we generated a mouse model with an intestinal epithelial-specific knockout of NM IIA heavy chain (NM IIA cKO) and examined the structure and function of normal gut barrier, and the development of experimental colitis in these animals. Unchallenged NM IIA cKO mice showed increased intestinal permeability and altered expression/localization of several AJ/TJ proteins. They did not develop spontaneous colitis, but demonstrated signs of a low-scale mucosal inflammation manifested by prolapses, lymphoid aggregates, increased cytokine expression, and neutrophil infiltration in the gut. NM IIA cKO animals were characterized by a more severe disruption of the gut barrier and exaggerated mucosal injury during experimentally-induced colitis. Our study provides the first evidence that NM IIA plays important roles in establishing normal intestinal barrier, and protection from mucosal inflammation in vivo.
Highlights
Establishment of the intestinal epithelial barrier is a fundamental feature of healthy gut, protecting the body from the harmful contents of the gut lumen, and allowing for the regulated bidirectional transport of fluids, nutrients, and waste
The only phenotypic abnormality of NM IIA cKO mice was the development of rectal prolapses that were observed in approximately 52% of non muscle myosin II (NM II) cKO mice, but not in NM IIA+/+ or heterozygous animals (Fig. 1B, Table 1)
The present study provides the first evidence that NM IIA acts as a positive regulator of the intestinal epithelial barrier in normal gut and suppresses intestinal mucosal inflammation in vivo
Summary
Establishment of the intestinal epithelial barrier is a fundamental feature of healthy gut, protecting the body from the harmful contents of the gut lumen, and allowing for the regulated bidirectional transport of fluids, nutrients, and waste. Perijunctional actin filaments are enriched in non muscle myosin II (NM II), a motor protein that converts the chemical energy of ATP hydrolysis into mechanical forces, mediating cytoskeletal tension and contractility This protein works as a molecular ensemble consisting of two heavy chains, two essential, and two regulatory myosin light chains (RMLC)[14,15]. Evidence exist that MLCK can modulate junctional permeability in inflamed tissue via NM II-independent mechanisms involving integrin signaling[31] These examples emphasize the need for more specific experimental approaches to examine the effects of NM II activity on the integrity of epithelial barriers in vivo. This study demonstrates, for the first time, that intestinal epithelial NM IIA controls the integrity of mucosal barrier in healthy gut in vivo, and limits the development of experimental colitis
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