Abstract
Platelets comprise a highly interactive immune cell subset of the circulatory system traditionally known for their unique haemostatic properties. Although platelets are considered as a vault of growth factors, cytokines and chemokines with pivotal role in vascular regeneration and angiogenesis, the exact mechanisms by which they influence vascular endothelial cells (ECs) function remain underappreciated. In the present study, we examined the role of human IL-17A/IL-17RA axis in platelet-mediated pro-angiogenic responses. We reveal that IL-17A receptor (IL-17RA) mRNA is present in platelets transcriptome and a profound increase is documented on the surface of activated platelets. By quantifying the protein levels of several factors, involved in angiogenesis, we identified that IL-17A/IL17RA axis selectively induces the release of vascular endothelial growth factor, interleukin -2 and -4, as well as monocyte chemoattractant protein -1 from treated platelets. However, IL-17A exerted no effect on the release of IL-10, an anti-inflammatory factor with potentially anti-angiogenic properties, from platelets. Treatment of human endothelial cell two-dimensional tubule networks or three-dimensional spheroid and mouse aortic ring structures with IL-17A-induced platelet releasate evoked pro-angiogenic responses of ECs. Our findings suggest that IL-17A may critically affect platelet release of pro-angiogenic factors driving ECs towards a pro-angiogenic state.
Highlights
Platelets are highly interactive components of the circulatory system with welldocumented haemostatic properties
Capillary Tube Formation Assay houfmhuanmuamn buimlicbaillivceailnveenindoetnhdeloiathl elial cells cells (HUVECs) (12 × 104), inoculated with either vascular endothelial growth factor (VEGF), IL-17A or stimulated platelet releasate from 2 × 108/mL, as indicated, were cultured in a 12-well plate (Greiner, Kremsmünster, Austria) coated with 200 μL Matrigel Basement Membrane Matrix (BD Biosciences, San Jose, CA, USA), as we have previously described [55]
Platelet surface expression of IL-17 receptor A (IL-17RA) was determined by flow cytometry in platelets stimulated with ADP, TRAP14 or PAR4-AP as well as in platelets treated with PBS
Summary
Platelets are highly interactive components of the circulatory system with welldocumented haemostatic properties. Apart from VEGF and endostatin, platelets contain and secrete a plethora of growth factors and chemokines that are involved in induction or inhibition of vascular regeneration and angiogenesis, like the well-characterized for its pro-angiogenic potency, the stromal derived factor 1 alpha (SDF1α). IL-17A is a potent proinflammatory cytokine that acts on fibroblasts, stromal, epithelial, endothelial cells, as well as on monocytes, stimulating the secretion of proinflammatory mediators, including chemokines like CXCL1, CXCL5, CXCL8 (IL-8), CXCL12 (SDF-1) and CCL2 (MCP1) [48,49]; cytokines, like tumour necrosis factor alpha (TNF-α), granulocyte colony-stimulating factor (GCSF) and interleukin 1-beta [48,49,50]. We hypothesized that expression of the IL-17RA on the surface of platelets may influence the secretion of platelet molecules with functional repercussions for the endothelial cell pro-angiogenic switch
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