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Complement drives glucosylceramide accumulation and tissue inflammation in Gaucher disease
- Source :
- Nature. 543:108-112
- Publication Year :
- 2017
- Publisher :
- Springer Science and Business Media LLC, 2017.
-
Abstract
- Gaucher disease is caused by mutations in GBA1, which encodes the lysosomal enzyme glucocerebrosidase (GCase). GBA1 mutations drive extensive accumulation of glucosylceramide (GC) in multiple innate and adaptive immune cells in the spleen, liver, lung and bone marrow, often leading to chronic inflammation. The mechanisms that connect excess GC to tissue inflammation remain unknown. Here we show that activation of complement C5a and C5a receptor 1 (C5aR1) controls GC accumulation and the inflammatory response in experimental and clinical Gaucher disease. Marked local and systemic complement activation occurred in GCase-deficient mice or after pharmacological inhibition of GCase and was associated with GC storage, tissue inflammation and proinflammatory cytokine production. Whereas all GCase-inhibited mice died within 4-5 weeks, mice deficient in both GCase and C5aR1, and wild-type mice in which GCase and C5aR were pharmacologically inhibited, were protected from these adverse effects and consequently survived. In mice and humans, GCase deficiency was associated with strong formation of complement-activating GC-specific IgG autoantibodies, leading to complement activation and C5a generation. Subsequent C5aR1 activation controlled UDP-glucose ceramide glucosyltransferase production, thereby tipping the balance between GC formation and degradation. Thus, extensive GC storage induces complement-activating IgG autoantibodies that drive a pathway of C5a generation and C5aR1 activation that fuels a cycle of cellular GC accumulation, innate and adaptive immune cell recruitment and activation in Gaucher disease. As enzyme replacement and substrate reduction therapies are expensive and still associated with inflammation, increased risk of cancer and Parkinson disease, targeting C5aR1 may serve as a treatment option for patients with Gaucher disease and, possibly, other lysosomal storage diseases.
- Subjects :
- Male
0301 basic medicine
T-Lymphocytes
Antigen-Presenting Cells
Complement C5a
Inflammation
Biology
Glucosylceramides
C5a receptor
Proinflammatory cytokine
Mice
03 medical and health sciences
Immune system
medicine
Animals
Humans
Complement Activation
Receptor, Anaphylatoxin C5a
Autoantibodies
Gaucher Disease
Multidisciplinary
Complement System Proteins
medicine.disease
Complement system
Disease Models, Animal
030104 developmental biology
Gaucher's disease
Glucosyltransferases
Immunoglobulin G
Immunology
Cytokines
Glucosylceramidase
Female
medicine.symptom
Glucocerebrosidase
Subjects
Details
- ISSN :
- 14764687 and 00280836
- Volume :
- 543
- Database :
- OpenAIRE
- Journal :
- Nature
- Accession number :
- edsair.doi.dedup.....9c9c9d9463d64c3cf955a9612d18a5eb