OLFML3 Promotes IRG1 Mitochondrial Localization and Modulates Mitochondrial Function in Macrophages

Area of Science:

• Immunology
• Cell Biology
• Molecular Medicine

Background:

• Olfactomedin-like protein 3 (OLFML3) is part of the olfactomedin (OLF) protein family with largely unknown functions.
• Emerging research suggests OLFML3 involvement in antiviral immunity and cancer development.

Purpose of the Study:

• To elucidate the specific roles of OLFML3 in macrophage function and inflammatory responses.
• To investigate the molecular mechanisms by which OLFML3 influences macrophage activity and cellular homeostasis.

Main Methods:

• Utilized a lipopolysaccharide (LPS)- or *Pseudomonas aeruginosa*-induced acute lung injury (ALI) mouse model.
• Employed mass spectrometry to identify OLFML3-interacting proteins, focusing on immunoresponsive gene 1 (IRG1).
• Assessed mitochondrial function, including membrane potential (MMP) and reactive oxygen species (mtROS), and protein-protein interactions with AIFM1.

Main Results:

• OLFML3 depletion worsened inflammatory responses and reduced survival in an ALI mouse model.
• OLFML3 regulates macrophage phagocytosis and migration, crucial for *in vivo* activity.
• OLFML3 interacts with IRG1, promoting its mitochondrial localization via AIFM1, thereby maintaining mitochondrial homeostasis and itaconate metabolite levels.

Conclusions:

• OLFML3 plays a critical protective role in macrophages during acute lung injury.
• OLFML3 facilitates IRG1 mitochondrial import, preserving mitochondrial function and mitigating inflammatory damage.
• OLFML3 represents a potential therapeutic target for inflammatory lung diseases.