Signalling through Src family kinase isoforms is not redundant in models of thrombo-inflammatory vascular disease

The Src family kinases (SFK) are a group of signalling molecules with important regulatory functions in inflammation and haemostasis. Leucocytes and platelets express multiple isoforms of the SFKs. Previous studies used broad-spectrum pharmacological inhibitors, or murine models deficient in multiple SFK isoforms, to demonstrate the functional consequences of deficiencies in SFK signalling. Here, we hypothesized that individual SFK operate in a non-redundant fashion in the thrombo-inflammatory recruitment of monocyte during atherosclerosis. Using invitro adhesion assays and single SFK knockout mice crossed with the ApoE(-/-) model of atherosclerosis, we find that SFK signalling regulates platelet-dependent recruitment of monocytes. However, loss of a single SFK, Fgr or Lyn, reduced platelet-mediated monocyte recruitment invitro. This translated into a significant reduction in the burden of atherosclerotic disease in Fgr(-/-)/ApoE(-/-) or Lyn(-/-)/ApoE(-/-) animals. SFK signalling is not redundant in thrombo-inflammatory vascular disease and individual SFK may represent targets for therapeutic intervention.