MAP Kinase Phosphatase 5 Protects Against Sepsis-induced Acute Lung Injury (112.10)

Abstract

Abstract Mitogen-activated protein kinases (MAPKs) play a critical role in inflammation. While activation of MAPK in inflammatory cells has been studied extensively, much less is known about the inactivation of these kinases. MAPK phosphatase 5 (MKP5) is a member of the dual specificity phosphatase family that dephosphorylates activated MAPKs. Here we report that MKP5 protects sepsis-induced acute lung injury. Mice lacking MKP5 displayed severe lung tissue damage following LPS challenge, characterized with increased neutrophil infiltration and edema compared to wild type controls. In response to LPS, MKP5-deficient macrophages produced significantly more inflammatory factors including inflammatory cytokines, nitric oxide (NO), and superoxide. Phosphorylation of p38 MAPK, JNK and ERK were enhanced in MKP5 deficient macrophages upon LPS stimulation. Adoptive transfer of MKP5-deficient macrophages led to more severe lung inflammation than transfer of WT macrophages, suggesting that MKP5-deficient macrophages directly contribute to acute lung injury. In addition, mice lacking MKP5 showed higher mortality rate than WT mice following cecal ligation and puncture (CLP), although MKP5 deficiency enhanced bacterial clearance by macrophages. Taken together, these results suggest that MKP5 is crucial to homeostatic regulation of MAPK activation as well as the balance of antimicrobial and inflammatory responses.