Interplay of GTPases and Cytoskeleton in Cellular Barrier Defects during Gut Inflammation

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.

IFN-γ drives inflammatory bowel disease pathogenesis through VE-cadherin–directed vascular barrier disruption

“…Tight and adherens junctions are the 2 major components of the apical junction complex of endothelial cells (8,60). In intestinal endothelial cells, tight junctions are composed of occludin, JAM-A, cingulin, and ZO-1, whereas adherens junctions are formed by VE-cadherin and β-catenin (6,60). ZO-1 was not altered in the presence of IFN-γ, indicating that adherens junctions with VE-cadherin may be the major determinant of endothelial cell barrier function in our context.…”

Tight junctions in the development of asthma, chronic rhinosinusitis, atopic dermatitis, eosinophilic esophagitis, and inflammatory bowel diseases

“…Data from an experimental colitis mouse model suggest that compromised epithelial integrity may play a role in intestinal diseases 167 . Although the precise triggering event involved in the breakdown of gut homeostasis is still a matter of debate, a correlation between permeability and gastrointestinal disease has been reported 168 . A variety of pathologic conditions can promote increased paracellular permeability with abnormal TJ structure as well as down‐regulation of TJs in IBD.…”

IFN-γ-response mediator GBP-1 represses human cell proliferation by inhibiting the Hippo signaling transcription factor TEAD

“…IFN-γ regulates many cellular processes including innate and acquired immune responses, host defense reactions, and exerts direct anti-tumorigenic effects [ 1 , 2 ]. The large GTPase human guanylate-binding protein 1 (GBP-1) is highly induced by IFN-γ and indicates activation of cells by this cytokine [ 3 , 4 ] in diseased tissues in inflammatory bowel diseases, colorectal carcinoma (CRC), and others [ 5 – 9 ].…”