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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 inflammation1. 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 expensive2 and still associated with inflammation3,4, increased risk of cancer5 and Parkinson disease6, targeting C5aR1 may serve as a treatment option for patients with Gaucher disease and, possibly, other lysosomal storage diseases.
The proinflammatory environment in Gaucher disease led us to determine its association with systemic and/or local complement activation in a mouse model of Gaucher disease containing heteroallelic mutations in Gba1, a point mutation and a knockout (Asp409Val/ knockout, that is, Gba19V/-)7. Markedly elevated C5a levels were found in sera from Gba19V/- mice compared with wild-type mice (Fig. 1a). Notably, only purified CD11b+F4/80+ macrophages and CD11c+CD11b+ dendritic cells (DCs) (Fig. 1b) from Gba19V/- mice produced C5a, suggesting local C5 production and generation of C5a. This was associated with increased C5aR1 expression on DCs (Fig. 1c, Extended Data Fig. 1a-c) and macrophages (Fig. 1d, Extended Data Fig. 1d-f) from the liver, spleen and lung of Gba19V/- mice....