Protease‐activated receptor signaling in intestinal permeability regulation

article

Pontarollo, Giulia
Mann, Amrit
Brandão, I.
Malinarich, Frano
Schöpf, Marie
Reinhardt, Christoph

10.1111/febs.15055

Protease‐activated receptor signaling in intestinal permeability regulation

Coagulation
Epithelial barrier function
Epithelium
Gastrointestinal cancer
Inflammatory bowel disease
Intestine
Microbial proteases
Microbiota
Protease-activated receptor
Tissue factor

2019-12-11T15:46:34Z
2019-12-11T15:46:34Z
2019

Protease-activated receptors (PARs) are a unique class of G-protein-coupled transmembrane receptors, which revolutionized the perception of proteases from degradative enzymes to context-specific signaling factors. Although PARs are traditionally known to affect several vascular responses, recent investigations have started to pinpoint the functional role of PAR signaling in the gastrointestinal (GI) tract. This organ is exposed to the highest number of proteases, either from the gut lumen or from the mucosa. Luminal proteases include the host's digestive enzymes and the proteases released by the commensal microbiota, while mucosal proteases entail extravascular clotting factors and the enzymes released from resident and infiltrating immune cells. Active proteases and, in case of a disrupted gut barrier, even entire microorganisms are capable to translocate the intestinal epithelium, particularly under inflammatory conditions. Especially PAR-1 and PAR-2, expressed throughout the GI tract, impact gut permeability regulation, a major factor affecting intestinal physiology and metabolic inflammation. In addition, PARs are critically involved in the onset of inflammatory bowel diseases, irritable bowel syndrome, and tumor progression. Due to the number of proteases involved and the multiple cell types affected, selective regulation of intestinal PARs represents an interesting therapeutic strategy. The analysis of tissue/cell-specific knockout animal models will be of crucial importance to unravel the intrinsic complexity of this signaling network. Here, we provide an overview on the implication of PARs in intestinal permeability regulation under physiologic and disease conditions.
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