p38 MAPK Activity Is Required to Prevent Hyperactivation of NLRP3 Inflammasome

Abstract

Inflammation contributes to the pathogenesis and morbidity of wide spectrum of human diseases. The inflammatory response must be actively controlled to prevent bystander damage to tissues. Yet, the mechanisms controlling excessive inflammatory responses are poorly understood. NLRP3 inflammasome plays an important role in innate immune response to cellular infection or stress. Its activation must be tightly regulated because uncontrolled inflammasome activation is associated with a number of human diseases. p38 MAPK signaling plays an essential role in the regulation of inflammation. The role of p38 MAPK in inflammatory response associated with the expression of proinflammatory molecules is known. However, the anti-inflammatory functions of p38 MAPK are largely unknown. In this study, we show that pharmacologic inhibition or genetic deficiency of p38 MAPK leads to hyperactivation of NLRP3 inflammasome, resulting in enhanced Caspase 1 activation and IL-1β and IL-18 production. The deficiency of p38 MAPK activity induced an increase of cytosolic Ca²⁺ and excessive mitochondrial Ca²⁺ uptake, leading to exacerbation of mitochondrial damage, which was associated with hyperactivation of NLRP3 inflammasome. In addition, mice with deficiency of p38 MAPK in granulocytes had evidence of in vivo hyperactivation of NLRP3 inflammasome and were more susceptible to LPS-induced sepsis compared with wild-type mice. Our results suggest that p38 MAPK negatively regulates NLRP3 inflammasome through control of Ca²⁺ mobilization. Hyperactivity of inflammasome in p38-deficient mice causes lung inflammation and increased susceptibility to septic shock.