Abstract
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 in vitro 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 in vitro. 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.
Highlights
Primary atherosclerosis is a chronic inflammatory, fibro-proliferative disease of the artery wall, in which arterial plaques of great cellular and molecular complexity develop over many years.[1]
Using in vitro adhesion assays and single Src family kinases (SFK) knockout mice crossed with the ApoEÀ/À model of atherosclerosis, we find that SFK signalling regulates platelet-dependent recruitment of monocytes
Direct evidence that thrombo-inflammatory pathways are relevant to the development of vascular disease comes from murine models of atherosclerosis, where inhibition of platelet adhesion, or induction of thrombocytopenia, significantly reduced the burden of atheroma.[5,36,37]
Summary
Primary atherosclerosis is a chronic inflammatory, fibro-proliferative disease of the artery wall, in which arterial plaques of great cellular and molecular complexity develop over many years.[1]. Non-redundant functions of Fyn have been identified in neuronal maturation and spatial learning in knockout animals,[20,21] leucocytes deficient in multiple SFK have been presumed necessary to remove redundant SFK signalling during leucocyte recruitment in inflammation Such a strategy inhibits the function multiple adhesion pathways, including the b1 and b2 integrins essential for leucocyte trafficking.[22,23,24] In addition, leucocyte functions that may be dependent on outside-in signals originating from ligand bound integrins are affected in SFK-deficient animals.[25,26] For example, initiation of the respiratory burst, degranulation and phagocytosis are known to be impaired in the absence of SFK signalling.[27,28] SFK are essential for platelet activation. We observed dramatic reductions in the burden of disease in the FgrÀ/À/ApoEÀ/À and LynÀ/À/ApoEÀ/À models of atherosclerosis
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