Sphingosine 1-phosphate receptor 3 regulates recruitment of anti-inflammatory monocytes to microvessels during implant arteriogenesis

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 110; no. 34; pp. 13785 - 13790
• Main Authors: Awojoodu, Anthony O., Ogle, Molly E., Sefcik, Lauren S., Bowers, Daniel T., Martin, Kyle, Brayman, Kenneth L., Lynch, Kevin R., Peirce-Cottler, Shayn M., Botchwey, Edward
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 20-08-2013; National Acad Sciences
• Subjects: Analysis of Variance; Animals; Biological Sciences; Biomedical materials; Blood; Blood vessels; Blotting, Western; Cells, Cultured; Chemotaxis; Chemotaxis - drug effects; Cytokines; Cytokines - secretion; DNA Primers - genetics; Drug Carriers; Endothelium; Fingolimod Hydrochloride; Flow Cytometry; Humans; Immunohistochemistry; Lactic Acid; Macrophages; Mice; Mice, Inbred C57BL; Microscopy, Confocal; Microvessels - cytology; Monocytes; Monocytes - drug effects; Monocytes - physiology; Neovascularization, Physiologic - drug effects; Neovascularization, Physiologic - physiology; Polyglycolic Acid; Propylene Glycols - administration & dosage; Propylene Glycols - pharmacology; Prostheses and Implants - adverse effects; Real-Time Polymerase Chain Reaction; Receptors; Receptors, Lysosphingolipid - agonists; Receptors, Lysosphingolipid - metabolism; Renovations; Secretion; Sphingosine - administration & dosage; Sphingosine - analogs & derivatives; Sphingosine - pharmacology; Thin films; Tissue engineering; Tissue Engineering - methods; Transplants & implants; Vascular System Injuries - drug therapy; Vascular System Injuries - etiology; Veins & arteries; immunomodulation; tissue engineering; biomaterials; sphingolipid; microvascular remodeling
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1221309110

Endothelial cells play significant roles in conditioning tissues after injury by the production and secretion of angiocrine factors. At least two distinct subsets of monocytes, CD45 ⁺CD11b ⁺Gr1 ⁺Ly6C ⁺ inflammatory and CD45 ⁺CD11b ⁺Gr1 ⁻Ly6C ⁻ anti-inflammatory monocytes, respond differentially to these angiocrine factors and promote pathogen/debris clearance and arteriogenesis/tissue regeneration, respectively. We demonstrate here that local sphingosine 1-phosphate receptor 3 (S1P ₃) agonism recruits anti-inflammatory monocytes to remodeling vessels. Poly(lactic-co-glycolic acid) thin films were used to deliver FTY720, an S1P ₁/₃ agonist, to inflamed and ischemic tissues, which resulted in a reduction in proinflammatory cytokine secretion and an increase in regenerative cytokine secretion. The altered balance of cytokine secretion results in preferential recruitment of anti-inflammatory monocytes from circulation. The chemotaxis of these cells, which express more S1P ₃ than inflammatory monocytes, toward SDF-1α was also enhanced with FTY720 treatment, but not in S1P ₃ knockout cells. FTY720 delivery enhanced arteriolar diameter expansion and increased length density of the local vasculature. This work establishes a role for S1P receptor signaling in the local conditioning of tissues by angiocrine factors that preferentially recruit regenerative monocytes that can enhance healing outcomes, tissue regeneration, and biomaterial implant functionality.