Table 1.
Key inflammatory mediators involved in VSMC-mediated atherosclerosis immunity.
| Cellular sources | Cellular targets | Roles in SMC dynamics | Impact in local immunity | Roles in atherosclerosis | References | |
|---|---|---|---|---|---|---|
| IL-1α | Apoptotic SMC, EC, T cell, macrophage | SMC, EC, monocyte | Activation, proliferation, remodeling | EC activation, monocyte influx | Damaging | |
| IL-1β | SMC, macrophage, DC, EC, platelet | SMC, EC, macrophage | Differentiation, proliferation, migration, ECM production, calcification, KLF4 expression | Monocyte/macrophage recruitment and activation, fibrous cap formation, adhesion molecule expression in EC, macrophage polarization | Damaging | (12) |
| IL-4 | Th2 cell, mast cell | SMC, macrophage, Th2 cell | Proliferation | Macrophage proliferation, M2 macrophage polarization, Th2 cell proliferation, and differentiation | Protective | (3) |
| IL-6 | Senescent SMC, EC, T cell, macrophage | SMC, EC, T cell, B cell | Inflammation, apoptosis, calcification | Monocyte influx, myeloid cell differentiation, activation | Controversial | (3, 13) |
| IL-8 | EC, monocyte, T cell | SMC, monocyte, neutrophil, T cell | Inflammation, apoptosis | Leukocyte retention | Damaging | |
| IL-17 | Th17 cell, gd T cell, NK cell, neutrophil | SMC, EC, macrophage, T cell | Inflammation, ECM destabilization | Leukocyte and neutrophil accumulation, EC adhesion molecule expression, MMP release | Controversial | (14) |
| IL-18 | SMC, EC, macrophage | SMC, EC, T cell, macrophage, NK cell | Adhesion molecule expression, ECM remodeling | Adhesion molecule expression, pro-inflammatory cytokine production | Damaging | |
| IFN-α | SMC, T cell, macrophage | SMC, EC, macrophage | Proliferation, migration, ECM remodeling | Adhesion molecule expression, cytokine production | Damaging | |
| TNF-α | SMC, T cell macrophage | SMC, monocyte, neutrophil, T cell | ECM production and remodeling, apoptosis, calcification | Neutrophil activation, proinflammatory cytokine production | Damaging | (15) |
| Chemokines | ||||||
| CCL-2/MCP-1 | SMC, EC, macrophage, T cell | SMC, monocyte, neutrophil | ECM remodeling, inflammation, migration | Monocyte recruitment and activation, neutrophil recruitment, pro-inflammatory cytokine release | Damaging | |
| CCL-19/21 | SMC | T cell, macrophage | ECM remodeling | T-cell and B-cell recruitment, proinflammatory cytokine release, macrophage egress | ATLO neogenesis, damaging | (13, 16, 17) |
| CXCL-12/SDF-1α | SMC, EC, macrophage, platelet | SMC, EC, monocyte, neutrophil | SMC progenitor recruitment, ECM remodeling | EC proliferation, adhesion molecule expression in EC, circulating progenitor recruitment, monocyte influx, plasma cell survival, neutrophil homeostasis, plaque stability | Protective | (18, 19) |
| CXCL-13 | SMC, macrophage | SMC, B cell, macrophage | Anti-apoptosis | B cell recruitment, maturation, proliferate, survival and affinity maturation, macrophage apoptosis, and polarization | ATLO neogenesis, Protective | (16, 20, 21) |
| CX3CL-1 | SMC, EC | SMC, T cell, monocyte, platelet | migration, survival | Monocyte/macrophage and T cell recruitment and adhesion, monocyte survival, platelet–monocyte complex formation | Damaging | |
| MIF | SMC, EC, macrophage, T cell | SMC, monocyte | Migration, EMC production, and remodeling | Monocyte influx | Damaging | |
| Growth factors | ||||||
| IGF-1 | SMC, EC | SMC, EC, macrophage | Proliferation, migration, apoptosis, ECM production | EC migration, survival, adhesion molecule expression, macrophage chemotaxis | Protective | (22) |
| PDGF-BB/DD | SMC, EC, platelet macrophage | SMC, EC, fibroblast | Differentiation, proliferation, migration, maturation, ECM production, KLF4 expression, autophagy, survival | EC dysfunction, leukocyte accumulation | Damaging | (23, 24) |
| TGF–β | SMC, EC, T cell, B cell, macrophage | SMC, EC, Treg, B cell | Differentiation, proliferation, migration, ECM production | Fibrous cap remodeling, EC activation, angiogenesis, anti-inflammatory cytokine production, wound healing | Protective | (25, 26) |
| Others | ||||||
| Lymphotoxin (TLO inducing cytokine) | Ly6Chi monocyte, T cell, LTi cell | SMC, EC, macrophage, T cell, B cell | SMC activation, trans-differentiation | Angiogenesis, stromal cell differentiation, leukocyte accumulation | TLO neogenesis, protective | (16, 27, 28) |
| CD-40L (costimulatory molecule) | SMC, EC, T cell, platelet | SMC, EC, macrophage, T cell | Activation, inflammation | Proinflammatory cytokine production, macrophage polarization, MMP release | Damaging | (13) |
| NLRP-3 (inflammasome) | SMC, macrophage | SMC, macrophage, neutrophil | ECM remodeling, inflammation | Macrophage priming, pro-inflammatory cytokine release | Damaging | (29) |
| Leukotrien-B4 (lipid mediator) | Macrophage, foam cell, dendritic cell | SMC, EC, macrophage | Proliferation, migration, ECM remodeling | EC activation, leucocyte chemotaxis, and activation | Damaging | |
| Annexin-A1 (lipid mediator) | EC, macrophage, neutrophil | SMC, neutrophil, T cell, macrophage | Migration, ECM production | Neutrophil and monocyte recruitment, apoptosis, phagocytosis, T cell activation, M2 macrophage, polarization | Protective | (13, 30) |
| Ephrin-A2 (guidance molecule) | SMC, EC, macrophage | SMC, EC, macrophage | proliferation, ECM production | Angiogenesis, fibrous cap thickness, monocyte adhesion | Damaging | |
| Netrin-1 (guidance molecule) | SMC, EC, macrophage | SMC, EC, macrophage | Migration, ECM remodeling | EC NO release, macrophage retention, leukocyte trafficking | Protective | (31, 32) |