Lactic acid suppresses MRGPRX2 mediated mast cell responses

Area of Science:

• Immunology
• Cell Biology
• Biochemistry

Background:

• MAS related G-protein coupled receptor X2 (MRGPRX2) is a GPCR on human mast cells involved in pseudo-allergic reactions and allergic diseases.
• Lactic acid, a metabolite, is elevated in inflamed tissues and influences immune cell function.
• Endogenous MRGPRX2 ligands and lactic acid are elevated in conditions like asthma and cancer.

Purpose of the Study:

• To investigate the role of lactic acid in regulating mast cell responses through MRGPRX2 and its mouse orthologue, MrgprB2.
• To determine if lactic acid can modulate mast cell activation pathways relevant to allergic and inflammatory conditions.

Main Methods:

• Mast cell activation assays (Ca2+ mobilization, degranulation, chemokine/cytokine release) using human (LAD2, skin) and mouse (peritoneal) mast cells.
• In vivo studies including passive systemic anaphylaxis and a mouse model of rosacea.
• pH-dependency studies of lactic acid's effects on mast cells.

Main Results:

• Lactic acid suppressed both early and late phases of mast cell activation in vitro.
• The suppressive effect of lactic acid on degranulation and cytokine release was pH-dependent in LAD2 cells.
• Lactic acid reduced anaphylaxis and skin inflammation in vivo, dependent on MrgprB2 expression.

Conclusions:

• Lactic acid acts as an inhibitor of mast cell activation via MRGPRX2.
• Lactic acid may play a protective role by dampening mast cell-mediated inflammation in asthma and cancer.
• Targeting lactic acid or its effects could be a therapeutic strategy for inflammatory and allergic diseases.