Review
Proteinase-activated receptors (PARs) in infection and inflammation in the gut

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Abstract

Proteinases have been shown to act as signaling molecules that are able to send specific signals to cells through the activation of proteinase-activated receptors (PARs). Those receptors which are expressed in a wide variety of cells in the gastrointestinal tract are considered as “emergency” mechanisms, particularly involved in inflammatory responses of the gut. Depending on the cell types of the gut in which PARs are activated, their activation interacts with all aspects of the gut physiology: motility, barrier function, transports, innate immune response, sensory functions, and even proliferation. A growing body of evidences discussed here suggests that these receptors, and the proteinases that activate them, are important mediators of the innate immune response of the gut and could play a major role in chronic inflammatory states of the gut (inflammatory bowel diseases), or infectious diseases.

Section snippets

PARs in the gut: expression and functions

Four members of this family of seven transmembrane domain G protein-coupled receptors have been cloned: PAR1 to PAR4. Some of the members of this family can be activated by the same proteinases: for example, PAR1, PAR3 and PAR4 are activated by thrombin, PAR2 and PAR4 are activated by trypsin, but others can show some specificity: for example, tryptase activates only PAR2 (Vergnolle, 2005) (see Table 1). PARs are expressed in intestinal epithelial cells (PAR1, PAR2, PAR4) (Mule, Pizzuti,

PARs in intestinal epithelium functions

In intestinal epithelial cells, PARs are expressed both on the apical and the basolateral surfaces, which suggests that it can be activated by different types of proteinases: luminal, circulating, secreted, of even membrane-associated proteinases. Both the apical and basolateral surfaces are potentially exposed to high concentrations of proteinases originating from the host, or from the gut flora.

Apical stimulation of intestinal epithelial monolayers by selective PAR1 agonists increases

PARs and intestinal immune cells

Evidences for functionality of PARs (PAR1, PAR2 and PAR3) in T-cells have been raised and studies on post-ligand signaling cascades have identified tyrosine phosphorylation of Vav1 as a common event to PAR activation in lymphocytes (Bar-Shavit et al., 2002). Other studies have shown that monocytic cells isolated from the lamina propria of mice can be stimulated by PAR1 or PAR2 selective agonists modifying the release of inflammatory cytokines (Fiorucci et al., 2001; Vergnolle et al., 2004). In

PARs and neuro-immune functions

Since the discovery that proteinases can signal to neurons through the activation of PARs (Steinhoff et al., 2000), and because of the strong expression of PAR1, PAR2 and PAR4 on enteric neurons (Gao et al., 2002; Kayssi, Amadesi, Bautista, Bunnett, & Vanner, 2007; Mule et al., 2004), the role of PARs as activators or modulators of neuro-immune functions has been more particularly studied. It has been established that PAR2 (Nguyen et al., 2003), but not PAR1 (Vergnolle et al., 2004) local

PAR-activating proteinases in the gut

Proteinases represent 2% of the human genome and are present at high concentrations, particularly in the gastrointestinal tract. Because of the potential harmful consequences of tissue exposure to high proteolytic activity, the release, activity and degradation of proteolytic enzymes must be tightly regulated. In order to be activated, PARs need to see active proteinases to be released in their vicinity and in a timely manner. Whether this release occurs in particular pathophysiological

Relevance of PARs in innate immune diseases of the gut

Crohn's disease and ulcerative colitis are chronic inflammatory disorders of the gut that affect mostly the large and small intestine. Although the etiology of the disease is still debated, the consensus hypothesis is that in genetically predisposed individuals, both environmental factors (luminal bacteria) and endogenous factors (defective immune response, defective intestinal barrier, hypo-responsive enteric nervous system) induce a mucosal immune response that is aberrant in either its

Concluding remarks

Because of the wide distribution of PARs in different cell types of the gut and the opposite effects that are sometimes observed: i.e.PAR1 activation on intestinal epithelial cells provokes apical chloride secretion, while PAR1 activation on enteric neurons suppresses luminal chloride secretion, it has been difficult to clearly define the role of each PARs in gut diseases. Depending on the tissues or cell types in which PARs are activated, and depending on the type of stimuli (chronic

Acknowledgments

NV is supported by an INSERM-Avenir grant, by the “Fondation Bettencourt-Schueller”, and by the “Institut UPSA de la Douleur”.

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