The role of Cl and K efflux in NLRP3 inflammasome and innate immune response activation.

Inflammation is part of innate immunity and is a natural response of the body to bacteria, virus, and any other pathogen infections or to damaged tissues. However, too much inflammation or chronic inflammation contributes to a wide variety of diseases such as inflammatory bowel disease, cancer, type 2 diabetes, heart disease, and autoimmune diseases such as rheumatoid arthritis. Recent studies underscored the critical role of K and Cl efflux in the activation of the inflammasome. The NLRP3 inflammasome is a multiprotein complex that mediates the production of the proinflammatory cytokines IL-1β and IL-18 and initiates the inflammatory cell death or pyroptosis. The NLRP3 inflammasome can be activated by multiple stimuli such as extracellular ATP, microbial toxins, ROS, mitochondrial DNA, or particulate matter. Although the precise mechanisms of NLRP3 activation and regulation by these diverse agonists remain unclear, multiple reports indicate that all NLRP3 agonists ultimately lead to a drop in intracellular concentration of potassium (K efflux) and chloride (Cl efflux). The WNK-SPAK/OSR1-[N]KCC pathway plays a critical role in maintaining K and Cl ion concentrations in the cell. Recent advances indicate that the WNK-SPAK-[N]KCC pathway plays a role in the activation of the innate immune response. This review highlights recent discoveries detailing how ion transport regulates innate immune cell response to inflammatory stimuli.