SEPTIN2 suppresses an IFN-γ-independent, proinflammatory macrophage activation pathway

Area of Science:

• Immunology
• Cell Biology
• Molecular Biology

Background:

• Interferon-gamma (IFN-γ) signaling is crucial for macrophage activation, but IFN-γ-independent pathways also contribute to inflammation.
• The precise mechanisms and triggers of IFN-γ-independent macrophage activation remain incompletely understood.

Purpose of the Study:

• To identify novel regulators of IFN-γ-independent macrophage autoactivation.
• To elucidate the molecular mechanisms by which SEPTIN2 (SEPT2) modulates macrophage inflammatory responses.

Main Methods:

• High-content screening was employed to identify regulatory proteins.
• Mechanistic studies focused on endoplasmic reticulum (ER) stress, SEPT2 expression, and protein modification (acetylation and ubiquitination) of heat shock protein 5 (HSP5).
• Analysis of M1-like polarization, proinflammatory cytokine release, and tissue damage.

Main Results:

• SEPTIN2 (SEPT2) was identified as a negative regulator of IFN-γ-independent macrophage autoactivation.
• Endoplasmic reticulum (ER) stress induces SEPT2 expression, which balances acetylation and ubiquitination of HSP5 at Lysine 327, thereby alleviating ER stress.
• Disruption of SEPT2-mediated regulation leads to unfolded protein accumulation, enhanced M1-like polarization, excessive inflammation, and tissue damage.

Conclusions:

• A novel IFN-γ-independent pathway for macrophage proinflammatory autoactivation regulated by SEPT2 has been uncovered.
• SEPT2 acts as a crucial negative feedback mechanism to constrain inflammation by managing ER stress and protein homeostasis.
• SEPT2 may represent a therapeutic target for preventing or resolving inflammation during infection.