Interferon-γ inhibits nonopsonized phagocytosis of macrophages via an mTORC1-c/EBPβ pathway

Area of Science:

• Immunology
• Molecular Biology
• Microbiology

Background:

• Viral infections can lead to secondary bacterial infections.
• Pulmonary interferon-gamma (IFN-γ) production during viral infections impairs macrophage phagocytosis.
• The precise molecular mechanisms underlying this impairment are not fully understood.

Purpose of the Study:

• To elucidate the molecular mechanisms by which IFN-γ inhibits macrophage phagocytosis.
• To investigate the role of the mTOR-c/EBPβ-MARCO pathway in IFN-γ-mediated phagocytosis.
• To evaluate the therapeutic potential of targeting this pathway to prevent secondary bacterial infections.

Main Methods:

• In vitro assays assessing macrophage phagocytosis of nonopsonized and opsonized targets.
• Analysis of MARCO, mTOR, and c/EBPβ expression and activity.
• In vivo studies using a mouse model of influenza and secondary bacterial infection.
• Pharmacological inhibition of mTOR using rapamycin.

Main Results:

• IFN-γ inhibited nonopsonized phagocytosis but enhanced opsonized phagocytosis.
• IFN-γ decreased MARCO expression and increased mTOR activity while decreasing c/EBPβ expression.
• MARCO blockade mimicked the inhibitory effect of IFN-γ on phagocytosis.
• Rapamycin reversed IFN-γ's inhibitory effects, restored protein expression, and protected mice from secondary bacterial infection.
• c/EBPβ was found to directly bind to the MARCO gene promoter.

Conclusions:

• IFN-γ inhibits nonopsonized macrophage phagocytosis via the mTOR-c/EBPβ-MARCO signaling pathway.
• mTOR is a key molecular target for preventing secondary bacterial infections following viral infections.
• Targeting the mTOR pathway offers a potential strategy to mitigate the detrimental effects of viral infections on host defense.