Transient Receptor Potential Vanilloid 4 (TRPV4) Regulates the Host Defense Response to Bacterial Pneumonia Through a MAPK Molecular Switch

Abstract

Abstract We have shown that macrophage activation in response to lipopolysaccharide (LPS) is sensitive to the biophysical properties of the matrix through the mechanosensitive channel, transient receptor potential vanilloid 4 (TRPV4). However, the signals that drive macrophage activation are not fully known. Studies suggest that LPS-induced macrophage activation is controlled in part by the MAPK pathway (i.e. p38, ERK, JNK). Thus, we investigated if TRPV4 mediates the macrophage response to LPS through MAPKs. In TRPV4 deleted BMDMs, p38 activation was decreased (69%) while JNK activation was increased (2-fold), and ERK was unchanged after LPS, in a matrix stiffness-dependent manner. Further studies reveal that activation of p38 enhances LPS-induced macrophage phagocytosis (2-fold), but blocks IL-1β secretion (2-fold); while JNK enhances secretion of IL-6, IL-8, and MIP-2 (2 fold). Hence, the TRPV4 and LPS signals synergizes to activate p38 which increases phagocytosis and limits IL-1β secretion while downregulating JNK activation to limit other pro-inflammatory cytokines. In order to evaluate the role of TRPV4 in chronic pneumonia/lung injury, WT and TRPV4 KO mice were intratracheally administered agarose-embedded P. aeruginosa. Loss of TRPV4 led to decreased phagocytosis/bacterial clearance (6-fold), increased lung inflammation as measured by inflammatory cell infiltration (80±3%), vascular permeability (63±6%), and pro-inflammatory cytokine secretion (IL-1β > by 71±4%). Thus, in the setting of lung infection TRPV4 functions to induce a molecular switch towards p38 which mediates bacterial clearance and downregulates pro-inflammatory cytokine secretion, to reduce infection-associated lung inflammation.