The cation channel TRPV4 is a central node in the regulation of lung responses to pathogens.

Pathogens accessing the airways release factors, such as endotoxins, that interact with receptors expressed in lining epithelial cells (ECs). This leads to responses that serve to avoid the damage of the epithelial integrity and further infection of the lungs. We have found that the lipopolysaccharide (LPS) from Gram-negative bacteria activates the cation channel TRPV4, expressed in the ECs. TRPV4 activation leads to a plethora of cellular effects that ultimately regulate LPS-induced leukocyte infiltration into mouse airways. Moreover, in preliminary experiments we proved that the sole activation of TRPV4 leads to cytokine production. These, together with the finding that LPS-induced activation of TRPV4 is independent from the canonical LPS receptor TLR4, led us to hypothesize that direct activation of TRPV4 by endotoxins or endogenous activators may play a role in both the activation threshold of ECs and in immune responses against pathogens. To test this hypothesis, this project aims at determining the molecular signaling pathway after TRPV4 activation in ECs. We will investigate how this activation threshold modification influences further responses to invading pathogens. We also aim at depicting the contribution of sensory nerves under health and disease conditions. By providing a unique and global overview of the airways, this project plans to unravel whether TRPV4 could constitute a novel target for the treatment of airway inflammation induced by bacterial infections.