ObjectiveSyk 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.MethodsPhosphorylation 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.ResultsWe 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.ConclusionThese 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.