Role of enteric nerves in immune-mediated changes in protease-activated receptor 2 effects on gut function

Protease-activated receptors (PARs) are expressed on structural and immune cells. Control of initiation, duration, and magnitude of PAR effects is linked to the level of receptor expression, availability of proteases, and the intracellular signal transduction machinery. We investigated nematode infection-induced changes in PAR(2) expression and the impact on smooth muscle and epithelial responses to PAR(2) agonists.

Smooth muscle and epithelial cell function were assessed in wild-type, and IL-4, IL-13 or STAT6 gene-deficient mice following treatment with vehicle, Nippostrongylus brasiliensis or Heligmosomoides polygyrus, or IL-13. The role of enteric nerves was determined using tetrodotoxin to block nerve conduction. Expression of PAR(2) was assessed by real-time PCR, western blot and immunohistochemistry.

Nematode infection induced a STAT6- and IL-13-dependent up-regulation of PAR(2) mRNA expression. The infection-induced hypercontractility to PAR(2) agonists required STAT6/IL-13 and was neurally mediated. In contrast, the infection-induced decrease in epithelial secretion to PAR(2) agonists was partly dependent on STAT6 and independent of enteric nerves. The hyposecretion was correlated with decreased PAR(2) immunofluorescent staining on the apical surface of epithelial cells, but enhanced lamina propria immunostaining for PAR(2).

This is the first study to demonstrate an immune regulation of PAR(2) expression that impacts both smooth muscle and epithelial cell responses to PAR(2) agonists. Differences in responses between smooth muscle and epithelial cells are related to the contribution of enteric nerves. These data provide a mechanism by which activation of PAR(2) in immune-based pathologies can induce both transient and long-lasting changes in gut function.