Research

C5a as a regulator of the inflammatory response in Gaucher disease

The complement system is well appreciated for its role as an important effector of innate immunity that is activated by the classical, lectin or alternative pathway. C5a is one important mediator of the system that is generated in response to canonical and non-canonical C5 cleavage by circulating or cell-derived proteases. In addition to its function as a chemoattractant for neutrophils and other myeloid effectors, C5a and its sister molecule C3a have concerted roles in cell homeostasis and surveillance. Through activation of their cognate G protein coupled receptors, C3a and C5a regulate multiple intracellular pathways within the mitochondria and the lysosomal compartments that harbor multiple enzymes critical for protein, carbohydrate and lipid metabolism. Genetic mutations of such lysosomal enzymes or their receptors can result in the compartmental accumulation of specific classes of substrates in this organelle summarized as lysosomal storage diseases (LSD). A frequent LSD is Gaucher disease (GD), caused by autosomal recessively inherited mutations in GBA1, resulting in functional defects of the encoded enzyme, acid β-glucosidase (glucocerebrosidase, GCase). Such mutations promote excessive accumulation of β-glucosylceramide (GC or GL1) in innate and adaptive immune cells frequently associated with chronic inflammation. In a joint effort with the Pandey lab at Cincinnati Children's Hospital, we ncovered an unexpected link between the C5a and C5a receptor 1 (C5aR1) axis and the accumulation of GL1 in experimental and clinical GD (Pandey et al. Nature 2017).

Figure 1. Model detailing the mutiple functions of the C5a/C5aR1 axis in Gaucher disease. (1) Mutations in GBA1, encoding defective GCase, result in the accumulation of GL1 and LGL1 in visceral macrophages and other innate and adaptive immune cells. (2) Findings from Nair et al. (Blood 2015)  suggest that DCs take up GL1 and LGL1 released from Gaucher cells, migrate to lymph nodes and present their cargo via CD1d to NKT cells. This initial trigger together with signals from B lymphocytes drive the activation and differentiation of NKT cells with a TFH signature that promote the differentiation of B lymphocytes into plasma cells and the production of GL1 and LGL1-specific IgG auto-antibodies. (3) In tissues and the circulation, such IgG auto-antibodies form GL1-ICs that activate the classical pathway of complement, eventually leading to systemic C5 cleavage and C5a generation. (4) In addition to direct complement GL1-IC can also bind to activating FcγRs expressed on phagocytes. FcgR aggregation induces local C5 production and non-canonical C5 proteolysis by a cell-specific protease leading to C5a formation. (5) The binding of systemically or locally-generated C5a to C5aR1 enhances the accumulation of GL1 and LGL1 within phagocytes through increased expression of GCS, driving a vicious cycle that fuels the autoimmune response directed against GL1 and LGL1. The interruption of this vicious cycle at the level of C5a/C5aR1 interaction is sufficient to massively reduce cellular GL1 and LGL1 accumulation and protect from death in genetic and pharmacologically-induced GD models (Pandey et al. Nature 2017). (6) Finally, activation of the C5a/C5aR1 axis in DCs upregulates costimulatory molecules (CD80/CD86/CD40) and drives the activation of NKT effector cells (NKTEff) with Th1 (IFN-γ) and Th17 (IL-17A/F) signatures eventually sparking chronic inflammation and tissue destruction in GD (from Pandey, Grabwoski and Köhl, Semin. Immunol. 2018).

This project aims to delineate the potential roles of the C5a/C5aR1 axis in the devlopment of GL1-specific auto-antibodies and neuroinflammation/degeneration associated with reduced GCase activity in Parkinson’s disease.


Figure 1. Model detailing the mutiple functions of the C5a/C5aR1 axis in Gaucher disease. (1) Mutations in GBA1, encoding defective GCase, result in the accumulation of GL1 and LGL1 in visceral macrophages and other innate and adaptive immune cells. (2) Findings from Nair et al. (Blood 2015) suggest that DCs take up GL1 and LGL1 released from Gaucher cells, migrate to lymph nodes and present their cargo via CD1d to NKT cells. This initial trigger together with signals from B lymphocytes drive the activation and differentiation of NKT cells with a TFHsignature that promote the differentiation of B lymphocytes into plasma cells and the production of GL1 and LGL1-specific IgG auto-antibodies. (3) In tissues and the circulation, such IgG auto-antibodies form GL1-ICs that activate the classical pathway of complement, eventually leading to systemic C5 cleavage and C5a generation. (4)In addition to direct complementGL1-IC can also bind to activating FcγRs expressed on phagocytes. FcγR aggregation induces local C5 production and non-canonical C5 proteolysis by a cell-specific protease leading to C5a formation. (5) The binding of systemically or locally-generated C5a to C5aR1 enhances the accumulation of GL1 and LGL1 within phagocytes through increased expression of GCS, driving a vicious cycle that fuels the autoimmune response directed against GL1 and LGL1. The interruption of this vicious cycle at the level of C5a/C5aR1 interaction is sufficient to massively reduce cellular GL1 and LGL1 accumulation and protect from death in genetic and pharmacologically-induced GD models (Pandey et al. Nature 2017). (6)Finally,activation of the C5a/C5aR1 axis in DCs upregulates costimulatory molecules (CD80/CD86/CD40) and drives the activation of NKT effector cells (NKTEff) with Th1 (IFN-γ) and Th17 (IL-17A/F) signatures eventually sparking chronic inflammation and tissue destruction in GD (from Pandey, Grabwoski and Köhl, Semin. Immunol. 2018).

References

1. M.K. Pandey, T.A. Burrow, R. Rani, L.J. Martin, D. Witte, K.D. Setchell, M.A. McKay, A.F. Magnusen, W. Zhang, B. Liou, J. Köhl*, G.A. Grabowski*. Complement drives glucosylceramide accumulation and tissue inflammation in Gaucher disease, Nature 2017 543:108-112.*shared senior-authorship

2. M. K. Pandey, G.A. Grabowksi, J. Köhl. An unexpected player in Gaucher disease:  the multiple roles of complement in disease development. Semin. Immunol. 2018 37:30-42.