Transient Receptor Potential (TRP) ion channels are known for their ability to sense and respond to environmental cues such as thermal, chemical and mechanical stimuli. The TRP Vanilloid 4 (TRPV4) protein has emerged as one of the most intensely studied family members, due to its wide expression and contribution to diverse cellular processes related to mechanotransduction (e.g., vascular shear, cell adhesion and osmosensation), inflammation, barrier function and secretion. Central to the diverse functional repertoire of TRPV4 is its ability to sense lipid metabolites produced downstream of receptors such as GPCRs and mechanosensitive Piezo channels. Clinical mutations cause early onset arthropathies, skeletal defects and neuropathic conditions. TRPV4 has also been a long-term therapeutic target for pain, arthritis, IBD, sepsis and cardiovascular or respiratory disorders such as lung edema.
To decipher how ion channels such as TRPV4 regulate complex signalling events, our current objective is to integrate unbiased proteomic, metabolomic and lipidomic profiling with traditional methods, super-resolution microscopy, and new functional readouts such as BRET-based genetic sensors to monitor dynamic protein interactions. The presented findings will focus on macrophages, where TRPV4 is known to modulate innate immunity and macrophage phenotype, yet the precise mechanisms are poorly understood. Using our integrated approach, functional knockout of TRPV4 in macrophages resulted in a striking proteomic shift. Further functional assessment revealed previously unappreciated roles for TRPV4 in metabolic pathways related to Irg1-itaconate and cGAS-STING signalling. Together, the findings advance our understanding of the connection between lipid-sensing and Ca2+ permeability to ROS homeostasis and mito-lyso health.
These new biological insights help to explain how TRPV4 promotes a balanced immune reaction in response to an inflammatory challenge and will support efforts to therapeutically target TRPV4.