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

Abstract

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 antiinflammatory 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.sphingolipid | microvascular remodeling | biomaterials | immunomodulation | tissue engineering

DNA Methyltransferase 1–Dependent DNA Hypermethylation Constrains Arteriogenesis by Augmenting Shear Stress Set Point

“…Moreover, DNMT1 inhibition trended toward improved perfusion recovery in aged (10 to 11 months old) Balb/c mice (Figure S8). Although a few previous studies have demonstrated increased arteriogenic capacity after such a delayed treatment,46, 78, 79 ours is the first to demonstrate an epigenetic mechanism. DNMT1 inhibition may also be clinically advantageous because it appears to avoid the so‐called Janus phenomenon, which refers to the conundrum created by the fact that proarteriogenic therapies also tend to promote atherosclerosis 80.…”

An update on the biology of sphingosine 1-phosphate receptors

“…In WT mice, treatment with FTY720 results in decreased circulating monocytes; however, use of the S1P 1/4/5 agonist, BAF312, yielded similar results, both at homeostasis and during EAE, indicating that S1P 3 is not the sole regulator of monocyte circulation ( 104 ). This could be a cell subtype-specifi c effect, or dependent on environment, as local administration of FTY720 appeared to enhance recruitment of anti-infl ammatory pro-angiogenic monocytes ( 105 ). This supports an earlier report that macrophage S1P 3 induces a pro-regenerative phenotype in a model of renal ischemia/reperfusion ( 106 ).…”

Francisella tularensis LVS Induction of Prostaglandin Biosynthesis by Infected Macrophages Requires Specific Host Phospholipases and Lipid Phosphatases

“…LPA stimulation results in calcium mobilization in human monocytes and inhibition of TNF-␣ production in LPStreated mice (62,63). In contrast, S1P can induce an anti-inflammatory macrophage phenotype, while S1P receptor 3 is required for recruitment of anti-inflammatory monocytes to atherosclerotic plaques (64,65). The contrasting results suggest that the effects of S1P and LPA are context dependent.…”