TRPV4 Regulates the Host Defense Response to Infection

Dr. Scheraga recently gave a talk about her research program upon receiving the American Thoracic Society’s Rising Star Award at the 2018 ATS International Conference. Rising Stars are basic and translational science researchers at the assistant professor or early associate professor level making waves in their fields.

By Rachel G. Scheraga, MD

In the laboratory of Mitchell Olman, MD, MA, staff in the Department of Inflammation and Immunity, we are interested in understanding how immune cells interact with the biophysical properties of the lung, such as stiffness. In work recently published in the Journal of Immunology, we showed that the mechanosensitive, calcium-permeable, plasma membrane ion channel named transient receptor potential vanilloid 4 (TRPV4) mediates macrophage clearance of bacteria/particles and secretes an anti-inflammatory cytokine profile.

Specifically, we found inhibition of TRPV4 by pharmacologic agents or downregulation/deletion of TRPV4 resulted in almost complete blockage of lipopolysaccharide (LPS)-stimulated macrophage phagocytosis in vitro and in vivo in a lung matrix stiffness-dependent manner. Overall, our data shows that TRPV4 is required for macrophage activation functions in response to LPS.

We now have new data that is applicable to human disease and describes a molecular mechanism by which TRPV4 acts in macrophages. Our working model suggests that the LPS and TRPV4 signals converge to mediate macrophage phenotypic change, resulting in clearance of bacteria and resolution of infection-associated lung injury.

Pharmacologic agents targeting TRPV4 are currently under development and in phase 1 clinical trials. Successful targeting of TRPV4 channel activity may lead to therapeutic approaches to treat bacterial pneumonia and associated acute respiratory distress syndrome.

Dr. Scheraga is an associate staff physician in the Respiratory Institute and holds a secondary appointment in the Lerner Research Institute Department of Inflammation and Immunity.