Journal
KIDNEY INTERNATIONAL
Volume 97, Issue 6, Pages 1196-1207Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.kint.2019.12.014
Keywords
ANCA; experimental models; glomerulonephritis; kinase inhibitors; SYK; vasculitis
Categories
Funding
- UK Medical Research Council [G0901997, MR/M018733/1]
- Wellcome Trust [097882/Z/11/Z]
- Vasculitis UK
- Imperial College Healthcare Charity
- Ken and Mary Minton Chair of Renal Medicine
- National Institute for Health Research Imperial Biomedical Research Centre
- Wellcome Trust [097882/Z/11/Z] Funding Source: Wellcome Trust
- MRC [MR/M018733/1, G0901997] Funding Source: UKRI
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The anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitides (AAV) are a group of life-threatening multisystem diseases characterized by necrotising inflammation of small blood vessels and crescentic glomerulonephritis. ANCA are thought to play a direct pathogenic role. Previous studies have shown that spleen tyrosine kinase (SYK) is phosphorylated during ANCA-induced neutrophil activation in vitro. However, the role of SYK in vivo is unknown. Here, we studied its role in the pathogenesis of experimental autoimmune vasculitis, a pre-clinical model of myeloperoxidase-ANCA-induced pauci-immune systemic vasculitis in the Wistar Kyoto rat. Up-regulation of SYK expression in inflamed renal and pulmonary tissue during early autoimmune vasculitis was confirmed by immunohistochemical and transcript analysis. R406, the active metabolite of fostamatinib, a small molecule kinase inhibitor with high selectivity for SYK, inhibited ANCA-induced pro-inflammatory responses in rat leucocytes in vitro. In an in vivo study, treatment with fostamatinib for 14 days after disease onset resulted in rapid resolution of urinary abnormalities, significantly improved renal and pulmonary pathology, and preserved renal function. Shortterm exposure to fostamatinib did not significantly affect circulating myeloperoxidase-ANCA levels, suggesting inhibition of ANCA-induced inflammatory mechanisms in vivo. Finally, SYK expression was demonstrated within inflammatory glomerular lesions in ANCA-associated glomerulonephritis in patients, particularly within CD68Dve monocytes/macrophages. Thus, our data indicate that SYK inhibition warrants clinical investigation in the treatment of AAV.
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