Function and regulation of thermosensitive ion channel TRPV4 in the immune system.

Transient receptor potential vanilloid sub-type 4 (TRPV4) is a six transmembrane protein that acts as a non-selective Ca2+ channel. Notably, TRPV4 is present in almost all animals, from lower eukaryotes to humans and is expressed in diverse tissue and cell types. Accordingly, TRPV4 is endogenously expressed in several types of immune cells that represent both innate and adaptive immune systems of higher organism. TRPV4 is known to be activated by physiological temperature, suggesting that it acts as a molecular temperature sensor and thus plays a key role in temperature-dependent immune activation. It is also activated by diverse endogenous ligands, lipid metabolites, physical and mechanical stimuli. Both expression and function of TRPV4 in various immune cells, including T cells and macrophages, are also modulated by multiple pro- and anti-inflammatory compounds. The results from several laboratories suggest that TRPV4 is involved in the immune activation, a phenomenon with evolutionary significance. Because of its diverse engagement in the neuronal and immune systems, TRPV4 is a potential therapeutic target for several immune-related disorders.

TRPV4 regulates mitochondrial Ca2+-status and physiology in primary murine T cells based on their immunological state.

T cell activation process is critically affected by temperature and intracellular Ca2+-signalling. Yet, the nature and the key molecules involved in such complex Ca2+-signalling is poorly understood. It is mostly assumed that ion channels present in the plasma membrane primarily regulate the cytosolic Ca2+-levels exclusively. TRPV4 is a non-selective Ca2+ channel which can be activated at physiological temperature. TRPV4 is involved in several physiological, pathophysiological process as well as different forms of pain. Here we demonstrate that TRPV4 is endogenously expressed in T cell and is present in the mitochondria of T cells. TRPV4 activation increases mitochondrial Ca2+-levels, and alters mitochondrial temperature as well as specific metabolisms. The TRPV4-dependent increment in the mitochondrial Ca2+ is context-dependent and not just passively due to the increment in the cytosolic Ca2+. Our work also indicates that mitochondrial Ca2+-level correlates positively with a series of essential factors, such as mitochondrial membrane potential, mitochondrial ATP production and negatively correlates with certain factors such as mitochondrial temperature. We propose that TRPV4-mediated mitochondrial Ca2+-signalling and other metabolisms has implications in the immune activation process including immune synapse formation. Our data also endorse the re-evaluation of Ca2+-signalling in T cell, especially in the light of mitochondrial Ca2+-buffering and in higher body temperature, such as in case of fever. Presence of TRPV4 in the mitochondria of T cell is relevant for proper and optimum immune response and may provide evolutionary adaptive benefit. These findings may also have broad implications in different pathophysiological process, neuro-immune cross-talks, and channelopathies involving TRPV4.