Modulation of visceral pain and inflammation by protease-activated receptors

Abstract

The gastrointestinal (GI) tract is exposed to a large array of proteases, under both physiological and pathophysiological conditions. The discovery of G protein-coupled receptors activated by proteases, the protease-activated receptors (PARs), has highlighted new signaling functions for proteases in the GI tract, particularly in the domains of inflammation and pain mechanisms. Activation of PARs by selective peptidic agonists in the intestine or the pancreas leads to inflammatory events and changes in visceral nociception, suggesting that PARs could be involved in the modulation of visceral pain and inflammation. PARs are present in most of the cells that are potentially actors in the generation of irritable bowel syndrome (IBS) symptoms. Activation of PARs interferes with several pathophysiological factors that are involved in the generation of IBS symptoms, such as altered motility patterns, inflammatory mediator release, altered epithelial functions (immune, permeability and secretory) and altered visceral nociceptive functions. Although definitive studies using genetically modified animals, and, when available, pharmacological tools, in different IBS and inflammatory models have not yet confirmed a role for PARs in those pathologies, PARs appear as promising targets for therapeutic intervention in visceral pain and inflammation processes.

Figure 1

Mechanism of activation of PARs. (a) Proteases cleave the extracellular N-terminus domain to release a new N-terminus domain that acts as a tethered ligand binding and activating the receptor to induce an intracellular signal. (b) Synthetic peptides corresponding to the tethered ligand domain can mimic the effects of the proteolytically cleaved N-terminal domain to specifically activate the receptor.

Figure 2

Presence of proteases in the GI tract. Trypsin is released in the lumen of the GI tract for digestive purposes, but can also be present deeper into the tissues released from endothelial or epithelial cells. Proteases of the coagulation cascade such as thrombin, factor Xa and VIIa can be released into the lumen or the GI tissues upon tissue damage. When they degranulate, mast cells release massive amounts of tryptase both in the gut lumen and vasculature. Neutrophils present either in the tissues or translocated in the lumen release cathepsin G. Epithelial cells are exposed to bacterial proteases from the luminal side.

Figure 3

Interactions of PARs with components of the pathogenesis of IBS. PAR₁ and PAR₂ are present on enterocytes, where their activation potentially induces an increase in permeability, which could lead to bacterial translocation, sepsis and inflammation, as well as hypersensitivity. Direct activation of PAR₁ and PAR₂ on enteric neurons interferes with nociceptive and motor functions. Activation of PARs on cells involved in inflammatory responses (mast cells, neutrophils, lymphocytes, macrophages, fibroblasts, endothelium or neuropeptides containing neurons) could lead to the generation of inflammatory mediators and provokes further signs of inflammation such as granulocyte recruitment and plasma extravasation. Ion secretion and potentially water flux disturbances (diarrhea) could be evoked by PAR activation on enterocytes, fibroblasts or enteric nerves. PAR activation in the central nervous system modulates nociceptive responses to peripheral stimulation, playing a potential role in hypersensitivity states and eventually (although never studied) in enteric motor dysfunctions. Activation of PARs on enterocytes, enteric neurons or lymphocytes by bacterial proteases from luminal or infiltrated pathogens could also participate in the generation of symptoms associated with IBS.