PRAK Promotes the Pathogen Clearance by Macrophage Through Regulating Autophagy and Inflammasome Activation

Ligu Mi,Yu Zhang,Yu Wang,Jia Wu,Yan Wang,Hui Xu,Hui Dai

doi:10.3389/fimmu.2021.618561

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.

Highlights

Phagocytosis mediated by macrophages plays an important role in the first line defense against invading pathogens
In analysis of the peritoneal macrophage compartment, we observed a significant reduction of the CD11b+F4/80+ population, from 64.1% in wild type mice to 21.9% in the knockout mice (Figure 1B)
The difference was no longer detected between the knockout mice and the littermate controls upon thioglycolate treatment (Figure 1B)

Summary

Introduction

Phagocytosis mediated by macrophages plays an important role in the first line defense against invading pathogens. This continuous process starts from the internalization of the microorganism, leading to phagosome formation. The phagosome is fused with hydrolytic enzyme-containing lysosomes to generate a phagolysosome. Several conditions favor bacterial elimination in the phagolysosome, including reactive oxygen species (ROS), reactive nitrogen species, lysozyme, and antibacterial inflammatory cytokines such as IFN-g [1].

Methods

Results

Conclusion