title: Complement drives glucosylceramide accumulation and tissue inflammation in Gaucher disease.
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.
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
authors.forename: Manoj K
authors.initials: MK
authors.lastname: Pandey
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Burrow
authors.affiliation: Division of Immunobiology and Center for Systems Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
authors.forename: Reena
authors.initials: R
authors.lastname: Rani
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
authors.forename: Lisa J
authors.initials: LJ
authors.lastname: Martin
authors.affiliation: Division of Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
authors.forename: David
authors.initials: D
authors.lastname: Witte
authors.affiliation: Laboratory of Mass Spectroscopy, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Setchell
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
authors.forename: Mary A
authors.initials: MA
authors.lastname: Mckay
authors.affiliation: Division of Immunobiology and Center for Systems Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
authors.forename: Albert F
authors.initials: AF
authors.lastname: Magnusen
authors.affiliation: Laboratory of Mass Spectroscopy, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
authors.forename: Wujuan
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Liou
authors.affiliation: Division of Immunobiology and Center for Systems Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.|Institute for Systemic Inflammation Research, University of Lübeck, 23562 Lübeck, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Köhl
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Grabowski
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000166:cytology / Q000276:immunology; D001323:Autoantibodies / Q000276:immunology; D003167:Complement Activation; D015936:Complement C5a / Q000096:biosynthesis / Q000276:immunology; D003165:Complement System Proteins / Q000096:biosynthesis / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D005776:Gaucher Disease / Q000276:immunology* / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control; D005962:Glucosylceramidase / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics; D005963:Glucosylceramides / Q000276:immunology* / Q000378:metabolism*; D005964:Glucosyltransferases / Q000096:biosynthesis / Q000378:metabolism; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control; D008297:Male; D051379:Mice; D044087:Receptor, Anaphylatoxin C5a / Q000172:deficiency / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology
chemical_list: D001323:Autoantibodies; C000591759:C5ar1 protein, mouse; D016207:Cytokines; D005963:Glucosylceramides; D007074:Immunoglobulin G; D044087:Receptor, Anaphylatoxin C5a; D015936:Complement C5a; D003165:Complement System Proteins; D005964:Glucosyltransferases; C023246:ceramide glucosyltransferase; D005962:Glucosylceramidase