Abstract
An essential role of the intestine is to build and maintain a barrier preventing the luminal gut microbiota from invading the host. This involves two coordinated physical and immunological barriers formed by single layers of intestinal epithelial and endothelial cells, which avoid the activation of local immune responses or the systemic dissemination of microbial agents, and preserve tissue homeostasis. Accordingly, alterations of epithelial and endothelial barrier functions have been associated with gut inflammation, for example during inflammatory bowel disease (IBD). The discriminative control of nutriment uptake and sealing toward potentially pathological microorganisms requires a profound regulation of para- and transcellular permeability. On the subcellular level, the cytoskeleton exerts key regulatory functions in the maintenance of cellular barriers. Increased epithelial/endothelial permeability occurs primarily as a result of a reorganization of cytoskeletal–junctional complexes. Pro-inflammatory mediators such as cytokines can induce cytoskeletal rearrangements, causing inflammation-dependent defects in gut barrier function. In this context, small GTPases of the Rho family and large GTPases from the Dynamin superfamily appear as major cellular switches regulating the interaction between intercellular junctions and actomyosin complexes, and in turn cytoskeleton plasticity. Strikingly, some of these proteins, such as RhoA or guanylate-binding protein-1 (GBP-1) have been associated with gut inflammation and IBD. In this review, we will summarize the role of small and large GTPases for cytoskeleton plasticity and epithelial/endothelial barrier in the context of gut inflammation.
Highlights
Epithelia at mucosal surfaces represent the first barrier preventing potentially harmful environmental factors to invade the host
Increased paracellular permeability and epithelial/ endothelial barrier dysfunction have been linked to the pathogenesis of chronic inflammatory disorders, such as inflammatory bowel diseases (IBDs) [2, 8, 9]
These intercellular junctions are connected to the actomyosin cytoskeleton via cytoplasmatic adaptors, such as zonula occludens (ZO) proteins, and catenins [6, 15, 16], which supports the mechanical strength of the junctions
Summary
Epithelia at mucosal surfaces represent the first barrier preventing potentially harmful environmental factors to invade the host. The epithelium does represent a simple physical obstacle against pathogen invasion but it regulates nutrient uptake and innate immune function by avoiding the activation of mucosal immune responses [1]. Thereby, maintenance of epithelial integrity is a key aspect in order to preserve homeostasis and to impair the development of inflammation in mucosal tissues [2]. In addition to the epithelium, the gut–vascular barrier (GVB) has been recently described as a new anatomical structure which builds a second protective barrier preventing the microbiota to enter the bloodstream while allowing the translocation of immune cells and antigens [3]. Barrier function of the epithelium as well as of the endothelium is
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