Complement drives glucosylceramide accumulation and tissue inflammation in Gaucher disease

Area of Science:

• Immunology
• Genetics
• Biochemistry

Background:

• Gaucher disease results from GBA1 mutations, leading to glucosylceramide (GC) accumulation in immune cells and chronic inflammation.
• The link between excess GC and tissue inflammation in Gaucher disease is not fully understood.

Purpose of the Study:

• To investigate the role of complement activation, specifically C5a and C5a receptor 1 (C5aR1), in Gaucher disease pathogenesis.
• To explore C5aR1 as a potential therapeutic target for Gaucher disease.

Main Methods:

• Studied GCase-deficient mice and pharmacologically inhibited GCase activity.
• Analyzed complement activation, GC accumulation, inflammation, and autoantibody formation.
• Investigated the impact of C5aR1 deficiency or inhibition on disease outcomes.

Main Results:

• GCase deficiency or inhibition caused significant complement activation, GC accumulation, inflammation, and cytokine production.
• Mice lacking both GCase and C5aR1, or wild-type mice with inhibited C5aR, showed protection and survived.
• GCase deficiency led to GC-specific IgG autoantibodies, driving C5a generation and C5aR1 activation, which sustains GC accumulation and immune cell activation.

Conclusions:

• Complement C5a/C5aR1 pathway activation is a key driver of GC accumulation and inflammation in Gaucher disease.
• Targeting C5aR1 may offer a novel therapeutic strategy for Gaucher disease and potentially other lysosomal storage disorders.