The Role of TRPV4 in Regulating Innate Immune Cell Function in Lung Inflammation

Abstract

Ion channels/pumps are essential regulators of innate immune cell function. Macrophages have been increasingly recognized to have phenotypic plasticity and location-specific functions in the lung. Transient receptor potential vanilloid 4 (TRPV4) function in lung injury has been shown to be stimulus- and cell-type specific. In the current review, we discuss the importance of TRPV4 in macrophages and its role in phagocytosis and cytokine secretion in acute lung injury/acute respiratory distress syndrome (ARDS). Furthermore, TRPV4 controls a MAPK molecular switch from predominately c-Jun N-terminal kinase, JNK activation, to that of p38 activation, that mediates phagocytosis and cytokine secretion in a matrix stiffness-dependent manner. Expanding knowledge regarding the downstream mechanisms by which TRPV4 acts to tailor macrophage function in pulmonary inflammatory diseases will allow for formulation of novel therapeutics.

Keywords: MAPK; TRPV4 (transient receptor potential vanilloid-4); innate immunity; lung inflammation and injury; macrophage.

Figure 1

Working model demonstrates that a mechanical signal through TRPV4 regulates the LPS response. Our data shows in the absence of an above threshold mechanical signal, TRPV4 does not influence the minimal LPS/TLR4 response, leading to low level phagocytosis/bacterial clearance, and resultant lung homeostasis. In the presence of an above threshold mechanical signal, TRPV4 modulates with the LPS/TLR4 response to increase phagocytosis and decrease pro-inflammatory cytokine secretion, thereby protecting the lung from infection-associated injury/ARDS (7). Adapted from original publication in The Journal of Immunology. Copyright^© 2020 The American Association of Immunologists, Inc.