title: Myeloid cell-mediated renal injury in rapidly progressive glomerulonephritis depends upon spleen tyrosine kinase.
abstract: Antibody-dependent activation of myeloid cells within the glomerulus plays a central role in rapidly progressive forms of glomerulonephritis. The spleen tyrosine kinase (Syk) is expressed by all leukocytes, except mature T cells, and is required for signalling via the B-cell receptor, Fc receptors, and some integrins. Syk has been proposed as a therapeutic target in glomerulonephritis. However, little is known of Syk activation in human kidney disease, while studies in experimental glomerulonephritis using non-selective Syk inhibitors require validation via conditional gene deletion. The current study addressed both of these important points. Syk activation (Tyr(525/526) phosphorylation) was examined in a cohort of 96 patients with different glomerulonephritides. Syk activation was evident in infiltrating leukocytes, mainly neutrophils and macrophages, in 36/40 cases of rapidly progressive glomerulonephritis. In contrast, non-proliferative diseases showed little or no Syk activation. Glomerular and interstitial cells exhibiting Syk activation correlated with renal function and systemic inflammation. Next, we examined mice with conditional Syk gene deletion in myeloid cells (Syk(My) ) versus Syk(f/f) littermate controls in nephrotoxic serum nephritis - a model of rapidly progressive glomerulonephritis. Control Syk(f/f) mice featured a transient neutrophil influx at 3 h and severe disease on day 9 of nephrotoxic serum nephritis, with crescent formation, macrophage infiltration, inflammation, kidney fibrosis, and renal dysfunction. In contrast, Syk(My) mice had significantly reduced neutrophil and macrophage infiltration despite equivalent glomerular deposition of humoral reactants. Syk(My) mice exhibited reduced crescent formation, inflammation, and fibrosis, with improved renal function on day 9 of nephrotoxic serum nephritis. In conclusion, Syk activation is prominent in infiltrating myeloid cells in human rapidly progressive glomerulonephritis, and functional studies demonstrate that Syk deletion in myeloid cells is protective in mouse nephrotoxic serum nephritis.
authors.affiliation: Department of Nephrology, Monash Medical Centre, Monash Health, Clayton, Victoria, Australia.|Monash University Department of Medicine, Monash Medical Centre, Clayton, Victoria, Australia.
authors.forename: Jessica
authors.initials: J
authors.lastname: Ryan
authors.affiliation: Department of Nephrology, Monash Medical Centre, Monash Health, Clayton, Victoria, Australia.|Monash University Department of Medicine, Monash Medical Centre, Clayton, Victoria, Australia.
authors.forename: Frank Y
authors.initials: FY
authors.lastname: Ma
authors.affiliation: Department of Nephrology, Monash Medical Centre, Monash Health, Clayton, Victoria, Australia.|Monash University Department of Medicine, Monash Medical Centre, Clayton, Victoria, Australia.
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Han
authors.affiliation: Department of Nephrology, Monash Medical Centre, Monash Health, Clayton, Victoria, Australia.|Monash University Department of Medicine, Monash Medical Centre, Clayton, Victoria, Australia.
authors.forename: Elyce
authors.initials: E
authors.lastname: Ozols
authors.affiliation: Department of Nephrology, Monash Medical Centre, Monash Health, Clayton, Victoria, Australia.|Monash University Department of Medicine, Monash Medical Centre, Clayton, Victoria, Australia.
authors.forename: John
authors.initials: J
authors.lastname: Kanellis
authors.affiliation: Department of Nephrology, Monash Medical Centre, Monash Health, Clayton, Victoria, Australia.|Monash University Department of Medicine, Monash Medical Centre, Clayton, Victoria, Australia.
authors.forename: Greg H
authors.initials: GH
authors.lastname: Tesch
authors.affiliation: Department of Nephrology, Monash Medical Centre, Monash Health, Clayton, Victoria, Australia.|Monash University Department of Medicine, Monash Medical Centre, Clayton, Victoria, Australia.
authors.forename: David J
authors.initials: DJ
authors.lastname: Nikolic-Paterson
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004789:Enzyme Activation / Q000502:physiology*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D055786:Gene Knockout Techniques; D005921:Glomerulonephritis / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000201:enzymology*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000072377:Syk Kinase
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse
keywords: JNK; crescent; inflammation; macrophage; neutrophil; platelets