GPR84 regulates pulmonary inflammation by modulating neutrophil functions

Area of Science:

• Immunology
• Pulmonology
• Pharmacology

Background:

• Acute lung injury (ALI) is a severe condition leading to hypoxic respiratory failure, often progressing to acute respiratory distress syndrome (ARDS) with high mortality.
• Uncontrolled inflammation, particularly involving neutrophils, is a key driver of ALI pathogenesis.
• Current treatments for ALI/ARDS are limited, necessitating novel therapeutic targets and a deeper understanding of disease mechanisms.

Purpose of the Study:

• To investigate the role of G protein-coupled receptor 84 (GPR84) in the development of acute lung injury.
• To explore GPR84's mechanism of action in regulating neutrophil function during ALI.
• To evaluate GPR84 as a potential therapeutic target for ALI/ARDS.

Main Methods:

• Analysis of GPR84 expression in bronchoalveolar lavage fluid cells from lipopolysaccharide (LPS)-induced ALI mouse models.
• Assessment of ALI severity, neutrophil infiltration, and oxidative stress in GPR84-deficient or GPR84-blocked mice.
• Investigation of signaling pathways (Lyn, AKT, ERK1/2) and NADPH oxidase assembly in neutrophils upon GPR84 activation.

Main Results:

• GPR84 expression was significantly upregulated in ALI mouse models.
• GPR84 deficiency or blockade markedly reduced lung inflammation, neutrophil infiltration, and oxidative stress in ALI mice.
• GPR84 activation stimulated reactive oxygen species production in neutrophils via Lyn, AKT, and ERK1/2 signaling pathways, promoting NADPH oxidase assembly.

Conclusions:

• GPR84 plays a critical role in mediating neutrophil function and exacerbating lung inflammation in acute lung injury.
• The findings highlight GPR84 as a key regulator of neutrophil-driven inflammatory responses in ALI.
• GPR84 emerges as a promising therapeutic target for the treatment of ALI and potentially ARDS.