Source: School of Life Sciences
Written by: School of Life Sciences
Edited by: Tan Rongyu, Wang Dongmei
Macrophages are versatile and plastic effector cells of the innate immune system. They are critical for host defense, inflammation resolution and wound healing. In response to micro-environmental signals, macrophages polarize into M1- (pro-inflammatory) and M2-like (anti-inflammatory) macrophages to maintain homeostasis. M1-like macrophages are triggered by the invasion of pathogenic microorganisms to produce numerous pro-inflammatory cytokines including tumor necrosis factor TNF-
a, interleukin (IL)-1
b, and IL-6, leading to bacterial killing and anti-viral responses. In contrast, M2-like macrophages are found to produce anti-inflammatory cytokines, triggering tissue restoration and wound healing. Over-activated M1-like macrophages promote inflammatory cytokines storm, whereas disorders of M2-like macrophages lead to tumor progression and metastasis. Thus, to maintain a balance of robust anti-pathogen immunity and tissue homeostasis, delicate mechanisms are required to safeguard macrophages polarization.
Recently, research teams of Prof. Jun Cui and Prof. Junjiu Huang from the School of Life Sciences, Sun Yat-sen Universitty cooperate to discover the novel molecular mechanisms of how ubiquitin-specific protease 19 (USP19) regulates macrophages polarization in inflammation resolution. USP19, on one hand, promotes global autophagy that clears mitochondrial reactive oxygen species (ROS) and down-regulates NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome activation. On the other hand, USP19 stabilizes inflammasome un-engaged NLRP3 and promotes its interactions with interferon regulatory factor 4 (IRF4), thereby preventing p62-dependent selective autophagic degradation of IRF4 and promoting M2-like macrophages polarization.
They established an alum-induced peritonitis model and found that Usp19 deficient mice showed robust inflammatory cytokines release, increased neutrophils recruitment and impaired M2-like macrophages polarization. Further study revealed that USP19 inhibited NLRP3 inflammasome activation by increasing autophagy flux and decreasing the generation of mitochondrial ROS. In addition, USP19 inhibited the proteasomal degradation of inflammasome-independent NLRP3 by cleaving polyubiquitin chains. USP19-stabilized NLRP3 promoted M2-like macrophages polarization by direct association with IRF4, thereby preventing its p62-mediated selective autophagic degradation.
Figure 1. A proposed working model to illustrate how USP19-NLRP3 axis switches inflammatory and anti-inflammatory response via autophagy.
Collectively, the researchers uncover an unexpected mechanism that USP19 switches the pro-inflammatory role of NLRP3 into an anti-inflammatory function and promotes IRF4-mediated M2-like macrophages polarization (Figure 1). As dysfunctions of macrophages polarization are implicated in numerous human diseases, future developments that target USP19 may have therapeutic potential in inflammation-associated diseases.
This work entitled "USP19 suppresses inflammation and promotes M2-like macrophages polarization by manipulating NLRP3 function via autophagy" was published in the prestigious immunology journal
Cellular & Molecular Immunology on October 23, 2020. Prof. Jun Cui and Prof. Junjiu Huang are the corresponding authors. Dr. Tao Liu, Dr. Liqiu Wang and Prof. Puping Liang are the co-first authors. This research is supported by the National Natural Science Foundation of China.
Link to the paper:
https://www.nature.com/articles/s41423-020-00567-7
