USP19 suppresses inflammation and promotes M2-like macrophage polarization by manipulating NLRP3 function via...

Area of Science:

• Immunology
• Cell Biology
• Molecular Biology

Background:

• Macrophage polarization is crucial for host defense and tissue repair, differentiating into M1 (proinflammatory) or M2 (anti-inflammatory) phenotypes.
• The precise molecular regulators of macrophage polarization remain incompletely understood.

Purpose of the Study:

• To elucidate the role of ubiquitin-specific protease 19 (USP19) in regulating macrophage polarization and inflammatory responses.
• To investigate the molecular mechanisms by which USP19 influences NLRP3 inflammasome activation and M2 polarization.

Main Methods:

• Investigated USP19's effect on macrophage polarization in vitro and in vivo.
• Analyzed USP19's impact on NLRP3 inflammasome activation, autophagy flux, and mitochondrial reactive oxygen species (ROS) generation.
• Examined USP19's interaction with NLRP3 and interferon regulatory factor 4 (IRF4).
• Utilized Usp19 knockout (Usp19-/-) mice for comparative analysis.

Main Results:

• USP19 was identified as an anti-inflammatory switch that inhibits inflammation and promotes M2-like macrophage polarization.
• USP19 suppressed NLRP3 inflammasome activation by enhancing autophagy and reducing mitochondrial ROS.
• USP19 stabilized NLRP3 by cleaving its polyubiquitin chains, preventing proteasomal degradation.
• USP19-mediated NLRP3 stabilization promoted M2 polarization via interaction with IRF4, inhibiting its autophagic degradation.
• Usp19-/- mice exhibited reduced M2 polarization and increased IL-1β secretion upon alum and chitin challenge.

Conclusions:

• USP19 plays a critical role in switching the proinflammatory function of NLRP3 to an anti-inflammatory one.
• USP19 promotes M2 macrophage polarization and suppresses inflammatory responses through novel mechanisms involving NLRP3 regulation.
• USP19 represents a potential therapeutic target for managing inflammatory conditions.