Glucosylceramide induced complement activation triggers inflammation in Gaucher disease (CCR5P.212)
| Autor: | Manoj Pandey, Stuart Tinch, Venette Inskeep, Wujuan Zhang, Kenneth Setchell, Jörg Köhl, Gregory Grabowski |
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| Rok vydání: | 2015 |
| Předmět: | |
| Zdroj: | The Journal of Immunology. 194:186.14-186.14 |
| ISSN: | 1550-6606 0022-1767 |
| Popis: | Gaucher disease (GD) happens due to mutations in GBA1, which causes a deficiency of acid β-glucosidase critical for degradation of glucosylceramide (GC) into glucose and ceramide. Macrophages (Mɸs) were mainly having this defect and associated with eminent expression of cytokines, chemokines, and recruitment of activated immune cells in GD. The mechanism by which GC triggers such inflammation is still wanted. Excess of GC storage in dendritic and T cells has been reported to be the reason for their activation and production of inflammatory cytokines in Gba1 mouse model (D409V/null; 9V/null). Here, we have identified elevated expression of C5a and C5aR on 9V/null mice APCs. We therefore, hypothesized that GC induced C5a elicits immune inflammation in GD. To confirm this, conduritol B epoxide (CBE), induced chemical model of GD was developed in WT and C5aR-/- mice. We found that C5aR-/- mice were protected from CBE-induced GD development, which was associated with prolonged survival, marked reduction of GC, DCs and T cells positivity for CD40, CD80, CD86, CD40L, CD69, cytokines-chemokines secretion, immune cells recruitment, and decreased loss of red blood cells (RBCs) and platelets. Pharmacological blocking of C5aR in 9V/null mice showed marked reduction in several of these GD manifestations. Our data suggest that GC induced C5a contributes in disease development and targeting C5a signaling may have therapeutic potential for GD. |
| Databáze: | OpenAIRE |
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