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Published on: July 28, 2015
PRAK Promotes the Pathogen Clearance by Macrophage Through Regulating Autophagy and Inflammasome Activation
Ligu Mi1,2, Yan Wang1, Hui Xu3
1Department of Immunology, School of Basic Medical Sciences, National Health Commission (NHC) Key Laboratory of Medical Immunology, Peking University, Beijing, China.
Abstract:
The p38 regulated/activated protein kinase (PRAK) is a protein kinase downstream of p38MAPK. The present study investigated its function in the macrophage. Myeloid-specific deletion of Prak resulted in a significant reduction in F4/80+CD11b+ peritoneal macrophages with decreased expression of MHC-II and CD80. Upon infection with Listeria monocytogenes, Prak-deficient mice demonstrated an increased mortality, which was accompanied by a higher bacterial load in multiple tissues and elevated levels of proinflammatory cytokines in the serum. While the Prak-deficient macrophage showed similar potency in phagocytosis assays, its bactericidal activity was severely impaired. Moreover, Prak deficiency was associated with defects in ROS production, inflammasome activation as well as autophagy induction. Therefore, PRAK critically contributes to the clearance of intracellular pathogens by affecting multiple aspects of the macrophage function.
Insights
The p38 regulated/activated protein kinase (PRAK) is crucial for macrophage function in fighting infections. PRAK deficiency impairs bacterial clearance and increases susceptibility to pathogens like Listeria monocytogenes.
Area of Science:
- Immunology
- Cell Biology
- Molecular Biology
Background:
- p38 regulated/activated protein kinase (PRAK) is a downstream kinase of p38MAPK.
- The role of PRAK in macrophage function remains largely unexplored.
Purpose of the Study:
- To investigate the function of PRAK in macrophages.
- To determine PRAK's role in host defense against intracellular pathogens.
Main Methods:
- Generated myeloid-specific Prak-deficient mice.
- Assessed macrophage populations, phenotype, and function.
- Infected mice with Listeria monocytogenes and evaluated host survival, bacterial load, and cytokine levels.
- Investigated ROS production, inflammasome activation, and autophagy in Prak-deficient macrophages.
Main Results:
- Myeloid-specific Prak deletion reduced peritoneal macrophages (F4/80+CD11b+) with decreased MHC-II and CD80 expression.
- Prak-deficient mice exhibited increased mortality, higher bacterial burden, and elevated proinflammatory cytokines after L. monocytogenes infection.
- Prak-deficient macrophages showed impaired bactericidal activity, defective ROS production, inflammasome activation, and autophagy.
Conclusions:
- PRAK is essential for macrophage-mediated clearance of intracellular pathogens.
- PRAK influences multiple macrophage functions, including phagocytosis, bacterial killing, ROS generation, inflammasome activation, and autophagy.
- PRAK plays a critical role in the innate immune response to bacterial infection.
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