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A2.22 Tyrosine Phosphorylation Pathways in Myeloid Cell-Mediated Inflammatory Diseases
  1. M Kovács,
  2. T Németh,
  3. K Futosi,
  4. Z Jakus,
  5. C Sitaru,
  6. A Mócsai
  1. Department of Physiology, Semmelweis University School of Medicine, Budapest, Hungary; Department of Dermatology, University of Freiburg, Germany

Abstract

Background Tyrosine kinases are major therapeutic targets in cancer but their role in immune-mediated disease pathogenesis is less understood.

Methods Here we tested the role of tyrosine kinases and tyro sine kinase substrates in two autoantibody-mediated disease models, the K/BxN serum-transfer arthritis and anti-collagen VII autoantibody-induced blistering skin diseases.

Results Mice genetically deficient of the Syk tyrosine kinase in the hematopoietic compartment were completely protected from autoantibody-induced arthritis and blistering skin disease. Mice lacking three myeloid-specific tyrosine kinases (Hck, Fgr and Lyn) or the tyrosine kinase substrate PLCγ 2 were also protected from autoantibody-induced diseases. In vitro, Src-family kinases were required for Syk activation by immune complexes and both were further required for activation of PLCγ 2. The Src-family–Syk–PLCγ 2 pathway mediated cytokine production by myeloid cells but not neutrophil or monocyte migration per se. Lineage-specific analyses revealed that during autoantibody-induced arhritis, this signalling pathway was required in myeloid cells (particular neutrophils) but not in mast cells or platelets. Finally, Src-family kinases were also required for activation of myeloid cells by monosodium urite crystals and their deficiency attenuated monosdium urate crystal-induced arthritis, indicating that the role of this signalling pathway is not restricted to autoantibody-mediated disease processes.

Conclusions Taken together, the Src-family–Syk–PLCγ 2 pathway is an important component of both autoantibody-mediated and autoantibody-independent inflammatory disease processes.

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