Role of the Spleen Tyrosine Kinase Pathway in Driving Inflammation in IgA Nephropathy

Abstract

IgA nephropathy is the most common type of primary glomerulonephritis worldwide. At least 25% of patients may progress to kidney failure requiring dialysis or transplantation. Treatment of IgA nephropathy using generalized immunosuppression is controversial, with concerns regarding the balance of safety and efficacy in a nonspecific approach. This review describes the recent scientific evidence, and a current clinical trial, investigating whether spleen tyrosine kinase (SYK) may be a novel and selective therapeutic target for IgA nephropathy. SYK, a cytoplasmic tyrosine kinase, has a pivotal role as an early intermediate in intracellular signal transduction cascades for the B-cell receptor and the immunoglobulin Fc receptor, and thus is critical for B-cell proliferation, differentiation, and activation, and for mediating proinflammatory responses after Fc-receptor engagement in various cell types. In renal biopsy specimens of patients with IgA nephropathy, increased expression and phosphorylation of SYK were detected, and this correlated with the histologic features of mesangial and endocapillary proliferation. In cell culture studies, patient-derived IgA1 stimulated mesangial cell SYK activation, cell proliferation, and cytokine production, and these responses were attenuated by pharmacologic or molecular inhibition of SYK. A global, randomized, double-blind, placebo-controlled trial investigating the safety and efficacy of fostamatinib (an oral prodrug SYK inhibitor) in the treatment of patients with IgA nephropathy is ongoing, which may provide important evidence of the safety and efficacy of targeting this pathway in clinical disease.

Trial registration: ClinicalTrials.gov NCT02112838.

Keywords: B cell; Fc receptor; Glomerulonephritis; cell signaling; mesangial cell; tyrosine kinase.

Copyright © 2018. Published by Elsevier Inc.

Figures

Figure 1

SYK structure and activation. (A) Schematic diagram showing the multidomain structure of SYK. (B) Schematic diagram of the linker-kinase sandwich conformation that has been suggested for inactive resting SYK. (C-E) SYK activation after interaction with ITAM. (C) Unengaged receptor bearing nonphosphorylated ITAM motif within the cytoplasmic domain. (D) Upon receptor engagement by corresponding ligand, Src family kinases (SRC) phosphorylate (P) tyrosine residues within the ITAM motif. (E) Phosphorylated ITAM acts as a docking site for the SH2 domains of SYK, resulting in conformational change, autophosphorylation and transphosphorylation of SYK tyrosine residues, and subsequent activation of downstream targets. Reprinted with permission from McAdoo and Tam.

Figure 2

SYK expression in IgA nephropathy. (A) Immunoperoxidase staining for total SYK, showing SYK expression within an area of endocapillary glomerular proliferation and in distal tubular epithelial cells in a patient with IgA nephropathy. (B) Correlation of T-SYK detection with findings of mesangial proliferation (M1) and endocapillary proliferation (E1) in a cohort of patients with IgA nephropathy. ⁎P < 0.01. GCS,glomerular cross section. Reprinted with permission from McAdoo et al.

Figure 3

SYK activation and cytokine production by human mesangial cells after stimulation with patient-derived IgA1. (A) Time course of SYK activation (phosphorylation) in mesangial cells after stimulation by patient-derived IgA1. (B) Cytokine production by mesangial cells after stimulation by patient-derived IgA1, and dose-dependent reduction in cytokine production after incubation with selective SYK inhibitor R406, the active metabolite of fostamatinib. ⁎P < 0.05. IP, interferon gamma-induced protein 10. Reprinted with permission from Kim et al. Copyright 2012, the American Association of Immunologists, Inc.

Figure 4

SYK inhibition in experimental autoimmune glomerulonephritis (EAG). (A) Reversal of glomerular injury after introduction of fostamatinib (Fosta) treatment at day 18 (D18) in EAG. By day 36 (D36) in vehicle-treated animals, there was progression of renal injury, whereas in fostamatinib-treated animals there was improvement in glomerular injury. (B) Representative histopathologic findings at day 18, and at day 36 after introduction of fostamatinib or vehicle treatment at day 18, showing established crescentic glomerulonephritis at day 18, with progression to circumferential fibrocellular crescent formation in vehicle-treated animals, and reversal to essentially normal glomerular findings in fostamatinib-treated animals. Upper panels show hematoxylin and eosin–stained sections; lower panels were stained with Jones methenamine silver stain to delineate glomerular and tubular basement membranes. ⁎⁎P < 0.01; ⁎⁎⁎P < 0.001. Reprinted with permission from McAdoo et al.