The Regulation And Mechanism Of FXYD3 In NLRP3 Inflammasome Activation In Macrophage

NLRP3 inflammasome,a key regulator of innate and adaptive immunity,responds to a surprisingly diverse set of stimuli,however,the underlying pathway and mechanisms by which these diverse danger signals activate the same molecular machinery remain poorly understood.How its activation is regulated remains to be elucidated.FXYD domain containing ion transport regulator 3?FXYD3?is a membrane protein that may regulate the function of Na⁺/K⁺ATPases.FXYD3 is mainly expressed in epidermis,breast,colon,stomach,prostate and so on.The function of FXYD3 in innate immunity and whether the function is dependent on sodium-potassium channel remained unknown.We aim at exploring the function and related mechanisms of FXYD3 in macrophages.We constructed myeloid-specific FXYD3 deficient(Lysm^creFXYD3^fl/fl)C57BL/6mice and built mouse model related to NLRP3 inflammasome activation,such as sepsis,peritonitis and obesity caused by high fat diet to investigate the regulation of FXYD3in macrophages.Specific knockout of FXYD3 in macrophages can significantly alleviate the inflammation in these models,which is manifested as decreased serum IL-1?,less infiltration of inflammatory cells and milder pathological changes caused by high-fat diet.FXYD3 deficiency also inhibited the caspase-1 maturation and IL-1?secretion triggered by the NLRP3 agonists ATP,nigericin,and alum in LPS-primed bone marrow derived macrophages.Here we studied that myeloid FXYD3 deficiency attenuated the activation of NLRP3 inflammasome both in vitro and in vivo.According to scientific literature report,the main function of FXYD3 is to regulate the function of sodium potassium pump and chloride ion channel.Potassium?K⁺?efflux is widely accepted as a universal requirement for NLRP3 inflammasome activation.We have to confirm whether FXYD3's contribution in NLRP3inflammasome activation depends on icon channel regulation.Our data showed that FXYD3 deficiency exert a negative regulatory effect independent of intracellular potassium concentration change.Its deficiency might reduce AMPK phosphorylation and cell autophagy which lead to the accumulation of reactive oxygen species.This deduction still needs more experimental results to support.However,the precise regulation mechanism still needs further investigation.Our findings establish FXYD3 as a positive modulator of NLRP3 inflammasome,providing a new potential target for the diagnosis and treatment of diabetes,gout and other inflammatory diseases.