Stephen P. McAdoo
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The importance of Spleen tyrosine kinase (Syk) as a potential therapeutic target in glomerulonephritis
Open Date: 2010-08-30
Close Date: 2014-02-28
Articles (11)
Year:
2023
Year:
2023
Year:
2023
Year:
2023
Year:
2023
Year:
2023
Year:
2023
Year:
2023
Year:
2023
Objective Syk is a cytoplasmic protein tyrosine kinase that plays a role in signaling via B cell and Fc receptors (FcR). FcR engagement and signaling via Syk is thought to be important in antineutrophil cytoplasm antibody (ANCA) IgG–mediated neutrophil activation. This study was undertaken to investigate the role of Syk in ANCA‐induced myeloid cell activation and vasculitis pathogenesis. Methods Phosphorylation of Syk in myeloid cells from healthy controls and ANCA‐associated vasculitis (AAV) patients was analyzed using flow cytometry. The effect of Syk inhibition on myeloperoxidase (MPO)–ANCA IgG activation of cells was investigated using functional assays (interleukin‐8 and reactive oxygen species production) and targeted gene analysis with NanoString. Total and phosphorylated Syk at sites of tissue inflammation in patients with AAV was assessed using immunohistochemistry and RNAscope in situ hybridization. Results We identified increased phosphorylated Syk at critical activatory tyrosine residues in blood neutrophils and monocytes from patients with active AAV compared to patients with disease in remission or healthy controls. Syk was phosphorylated in vitro following MPO‐ANCA IgG stimulation, and Syk inhibition was able to prevent ANCA‐mediated cellular responses. Using targeted gene expression analysis, we identified up‐regulation of FcR‐ and Syk‐dependent signaling pathways following MPO‐ANCA IgG stimulation. Finally, we showed that Syk is expressed and phosphorylated in tissue leukocytes at sites of organ inflammation in AAV. Conclusion These findings indicate that Syk plays a critical role in MPO‐ANCA IgG–induced myeloid cell responses and that Syk is activated in circulating immune cells and tissue immune cells in AAV; therefore, Syk inhibition may be a potential therapeutic option.
Year:
2022
Year:
2022
Collaborators (61)
Bronwen Connolly
The Queen's University Belfast
Susanna Dunachie
Professor at University of Oxford
University of Oxford
Roger Thompson
Senior Lecturer
University of Sheffield
Benjamin H. Mullish
-
Jonathan Heeney
Professor of Comparative Pathology
University of Cambridge
Davies Adeloye
University of Edinburgh
Daniel Peckham
Professor or Respiratory Medicine
University of Leeds
Daniel Rea
Professor of Medical Oncology
University of Birmingham
Paul Moss
University of Birmingham
Tomoko Takano
Research Institute of the McGill University Health Centre
Antonia Ho
Clinical Senior Lecturer
MRC-University of Glasgow Centre For Virus Research
Brian Willett
Professor of Viral Immunology
University of Glasgow
Julio Saez-Rodriguez
-
Louise MacGillivray
University of Edinburgh
Masaomi Nangaku
Graduate School of Medicine, The University of Tokyo
Hamish McAuley
Academic Clinical Lecturer
University of Leicester
Cherie Armour
The Queen's University Belfast
Pilar Rivera-Ortega
Manchester University NHS Foundation Trust
Luke Daines
-
David R Baldwin
University of Nottingham
Petros Andrikopoulos
Assistant Professor, MRC Career Development Fellow
Imperial College London
Laura Merson
-
Donal Skelly
Academic Clinical Lecturer
University of Oxford
Tassos Grammatikopoulos
Honorary Clinical Senior Lecturer
King’s College London
Charlotte Bolton
Professor of Respiratory Medicine
University of Nottingham
Ryan Thwaites
Lecturer in Respiratory Immunology
Imperial College London
Timothy Wallis
Honorary Senior Clinical Lecturer
University of Southampton
Michael Gibbons
Honorary Associate Clinical Professor
University of Exeter
Jim Wild
Professor of Magnetic Resonance Physics
University of Sheffield
Stefan Siebert
Professor of Inflammation Medicine and Rheumatology
University of Glasgow
Karen Piper Hanley
The University of Manchester
Effrossyni Gkrania-Klotsas
Cambridge University Hospitals NHS Foundation Trust
Lucy Elizabeth Mary Finnigan
University of Oxford
Tao Dong
Ita Askonas Chaired professor for Translational Immunology
University of Oxford
Barbara Kronsteiner-Dobramysl
University of Oxford
Rachel Upthegrove
Professor of Psychiatry
University of Birmingham
Ewen Harrison
Director. Professor of Surgery and Data Science. Consultant Surgeon.
University of Edinburgh
Vicky Kamwa
University of Birmingham
John Sayer
Professor of Renal Medicine
Newcastle University
Joby Cole
Honorary Senior Clinical Lecturer
University of Sheffield
Manish Patel
Honorary Clinical Associate Professor
University of Glasgow
Michelle Holland
King’s College London
Robert Francis
King’s College London
Manish Pareek
Professor
University of Leicester
Joanna Porter
University College London
Alex Horsley
Professor
The University of Manchester
Matthew Broome
University of Birmingham
Sean Hua Lim
University of Southampton
Anthony Brown
University of Oxford
Ian Jarrold
Deputy Head of Research & Innovation
-
Mark Jones
Professor of Respiratory Medicine
University of Southampton
John Pearl
Lecturer
University of Leicester
ADRIAN HAYDAY
King’s College London
Eleanor Barnes
Professor of Hepatology and Experimental Medicine
University of Oxford
D. James Cooper
MONASH UNIVERSITY
Hector Chinoy
The University of Manchester
John Blaikley
The University of Manchester
Lance Turtle
Wellcome fellow/senior clinical lecturer
University of Liverpool
Tom Ward
Academic Clinical Lecturer
University of Leicester
Olivia Leavy
University of Leicester
Najib M Rahman
Professor of Respiratory Medicine
University of Oxford
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