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.

Metabolic Alterations in Human Peripheral Blood Mononuclear Cells Associate with Progression to Islet Autoimmunity and Type 1 Diabetes

“…Previous studies have shown that these glycosphingolipids modulate β-cell immune receptor signaling (Boslem et al, 2012;Osterbye et al, 2010) as well as aggravate systemic inflammation responses (Mobarak et al, 2018;Pandey et al, 2017). Elevated glycoceramide levels in PBMCs in autoantibody-positive children who later progress to T1D, as observed in our study, therefore point to a specific sphingolipid pathway in immune cells which contributes to T1D pathogenesis.…”

Sphingolipid metabolism in cancer signalling and therapy

“…In patients with Gaucher disease, who are susceptible to developing myeloma 25 , clonal immunoglobulin was reactive against lyso-glucosylceramide (an acyl group derivative of glucosylceramide) owing to a deficiency in glucocerebrosidase/glucosylceramidase, which is highly elevated in these patients 140 . Interestingly, in Gaucher disease, complement signalling via complement C5a and C5a receptor 1 (C5aR1) induced the accumulation of glucosylceramide and tissue inflammation 141 . Moreover, CERS6-generated C16 ceramide increased T cell response to alloantigens during allogeneic haematopoietic stem cell transplantation (allo-HSCT) in a mouse model of leukaemia, an effective immunotherapy for various haematological malignancies 142 .…”

Novel mechanisms and functions of complement

“…Although the connection of complement with another chronic bone loss disorder, periodontitis, was earlier suggested by correlative clinical studies, new interventional studies in non-human primates demonstrated a causative link between C3 activation and inflammatory periodontal bone loss 82,83 . Furthermore, complement was recently incriminated in Gaucher disease (GD), a genetically driven lysosomal storage disorder associated with dysregulated glycolipid metabolism in various tissues 84 . GD is associated with chronic inflammation marked by a pronounced autoimmune response to intracellularly accumulated glucosylceramide.…”

“…GD is associated with chronic inflammation marked by a pronounced autoimmune response to intracellularly accumulated glucosylceramide. Robust clinical evidence and data from animal studies implicated C5a-C5aR1 signaling in a vicious cycle that fuels chronic inflammation in GD through C5aR1-driven glycolipid accumulation and modulation of glucosylceramide-specific autoantibody generation 84 . Finally, the kidneys are particularly susceptible to damage induced by complement-mediated inflammation, which appears to drive various renal disorders (reviewed in refs.…”