Protease‐activated receptor signaling in intestinal permeability regulation

Abstract

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.

Serine proteases at the cutting edge of IBD: Focus on gastrointestinal inflammation

“…The uncontrolled exposure of colonic mucosa to such high trypsin levels was likely to cleave PAR‐2, a membrane‐spanning cell surface receptor that is believed to localize throughout the GI tract. PAR‐2 activation increased intestinal permeability thus promoting bacterial translocation from the gut lumen with a subsequent immune activation 65,66 . Coupling PAR‐2 processing (in response to trypsin or PAR‐2 agonists) with TJ rearrangements was then proposed to impair the barrier function and induce inflammation 67 .…”

Colonic paracellular permeability and circulating zonulin-related proteins

“…The proposed mechanism by which zonulin disablesTJ is dependent on the epidermal growth factor receptor (EGFR) and the protease-activated receptor (PAR2) [43]. These receptors have also shown to be expressed apically in the colonic mucosa [44]. Activation of disassembling TJ signaling pathway may not exclusively come from the apical side as both EGFR and PAR2 are present at the basolateral side of enterocytes [45].…”

A serine protease secreted from Bacillus subtilis cleaves human plasma transthyretin to generate an amyloidogenic fragment

“…Importantly, ageing is positively (and variably) related with increased permeability of the intestinal mucosa (often referred to as "leaky gut"), moderate chronic inflammatory state, and intestinal microbiota dysbiosis 61,62 . These changes are reciprocally connected, whereby alteration of the intestinal microbial composition increases intraluminal protease activity and, as a result, boosts self-enhanced paracellular permeability of the intestinal mucosa through proteolytic degradation of intercellular tight junction proteins or activation of protease-activated receptor 2 receptors [63][64][65][66] . The selective passage of (macro)molecules from the gut lumen to the systemic circulation is regulated by the Gut-Vascular Barrier, an anatomical/functional structure mainly formed by epithelial intestinal and endothelial vascular cells 67 .…”