TABLE 1.
Name, localization, and function of monocyte‐related cytokines/chemokines and their role in ischemic stroke.
| Name | Localization | Function in monocyte | Function in ischemic stroke | References |
|---|---|---|---|---|
| CCL2 (MCP‐1)/CCR2 | CCR2 is expressed in monocytes. CCL2 is secreted by many cells, including astrocytes, endothelial cells, neurons, and pericytes |
Monocyte migration from the bone marrow to the blood. Mediates monocyte migration to inflamed tissue |
Enhances the proinflammatory function of monocytes via P2X4R and promotes long‐term recovery of ischemic stroke. CCL2 promotes leukocyte crossing of the BBB and alters the expression of TJs in BMECs. CCL2/CCR2 binding induces conformational changes in VLA‐4. CCR2+ monocytes express high levels of VEGF‐A and can mediate the expression of PDGF beta and PDGF receptor beta mRNA in the ischemic state | [9, 15, 16, 18, 48, 52, 53, 54, 55, 56, 57, 65, 66, 67, 68] |
| CCR4 | Expressed on monocytes and T cells | May play a role in monocyte migration | CCR4 plays an important role in the polarization of macrophages/microglia | [73, 74, 75] |
| CCR5 | Expressed on intermediate monocytes | Mediates the migration of monocytes/MDMs | CCL5/CCR5 expression is increased in the ischemic hemisphere, which mediates the recruitment of Ly6C+ monocytes | [41, 74, 78] |
| CD36 (a highly glycosylated class B scavenger receptor) | Expressed in many cell types, including monocytes, macrophages, and microglia | Interacts with ligands to initiate inflammatory responses. Enhances the phagocytosis ability of microglia and monocytes/macrophages | CD36 cell surface expression is upregulated. CD36 may regulate monocyte recruitment by regulating CCL2/CCR2 expression. CD36 exacerbates brain injury in transient MCAO. CD36 may have a negative effect on the early phase of ischemic stroke, and reparative functions in the resolution phase | [32, 82, 84, 85] |
| CD40L (a transmembrane protein) | Expressed on activated platelets | Triggers the expression of adhesive molecules, such as E/P‐selectin and ICAM‐1, leading to the formation of platelet–leukocyte aggregates. Interacts with CD40 to stimulate IL‐1/6/8, TNF‐α, and MIP‐1α secretion in thrombosis | CD40L levels increase during the acute/subacute phase. CD40L expression is higher in small‐artery disease stroke than in cardioembolic stroke | [111, 115, 116, 117] |
| CX3CL1/CX3CR1 | CX3CL1 is produced by neurons. CX3CR1 is highly expressed in non‐classical monocytes | Required for the patrolling behavior of non‐classical monocytes. Activates integrins and has intrinsic adhesion properties | CX3CR1 may impact the volume of the infarcted area, the integrity of the BBB, angiogenesis, and neurological recovery | [21, 86, 87, 92, 93, 94] |
| CXCL12 (SDF‐1) | Produced by activated astrocytes | Regulates monocyte adhesion to BMECs | Recruits monocytes to infarcted tissue during the late stages of stroke | [34, 96] |
| ICAM‐1/LFA‐1 | ICAM‐1 is expressed on endothelial cells; LFA‐1 is expressed on monocytes | Required for the patrolling behavior of Ly6C− monocytes in the endothelium | Soluble ICAM‐1 is elevated, and high serum ICAM‐1 levels are associated with poor outcome | [18, 21, 97] |
| Ly6C | Highly expressed in classical monocytes | Marker of classical monocytes | Ly6Chi monocytes are involved in macrophage polarization. 98 Ly6Chi monocytes differentiate into M1 macrophages and secrete inflammatory cytokines. Ly6Clo monocytes have little impact on ischemic stroke | [1, 95, 98] |
| MMP‐2 | Secreted by monocytes | Involved in the secretion of chemokines, such as CCL2. Elevated during monocyte‐to‐macrophage differentiation | Early elevated MMP‐2 levels may be associated with better outcomes. Negative correlation between plasma MMP‐2 levels on admission and NIHSS scores. Patients with mild and improving symptoms have higher MMP‐2 levels. MMP‐2 is associated with BBB dysfunction and leukoaraiosis | [31, 101, 102, 103] |
| MMP‐9 | Secreted by monocytes | Involved in monocyte activation by interacting with soluble CD14, reducing monocyte responsiveness to LPS. Adipocyte fatty acid‐binding protein enhances JNK/c‐Jun activation, promoting MMP‐9 transactivation in peripheral monocytes (macrophages and microglia) and accelerating the breakdown of the BBB | Induces proinflammatory cytokines and chemokines, including CXCL8, IL‐1β, and TNF‐α. MMP‐9 damages BBB integrity by degrading TJs and the ECM to promote cerebral edema. Late elevated MMP‐9 levels are associated with poor outcome, whereas reduced MMP‐9 levels on admission are associated with better NIHSS scores | [5, 31, 101, 103] |
| NR4A1 | Expressed on monocytes | Essential for Ly6C− monocyte survival and the transition from Ly6C+ to Ly6C− monocytes. May be involved in monocyte‐to‐macrophage differentiation | Regulates neuroinflammation in cerebral ischemia by interacting with NF‐κB/p65. May be involved in microglial M1 polarization and CCL2/7 secretion | [11, 41, 101, 107, 108] |
| P2X4R | Highly expressed in immune cells | Activation of P2X4R+ cells, especially myeloid cells, releases proinflammatory cytokines, including IL‐1β/6 and TNF‐α, and may promote monocyte migration to the brain | P2X4R activation induces BDNF release, promoting monocyte polarization which secretes proinflammatory cytokines and chemokines and degrades TJs between endothelial cells and BBB | [9, 16, 19, 49] |
| P‐selectin | Resides in the alpha‐granule membrane of unstimulated platelets | Monocyte–platelet tethering. Binds to PSGL‐1 expressed on monocytes. Promotes monocyte secretion of CCL2, IL‐8, and TNF‐α, after tight adhesion, and deposition of platelet chemokines (CCL5/CXCL4) | Elevated P‐selectin levels during the acute/subacute phase are associated with ischemic stroke severity and outcome | [33, 87, 111, 112, 113, 114] |
| TLR2/TLR4 | TLR2/TLR4 are expressed in innate immune cells, such as monocytes | Recognize cell debris, pathogens, and microbial products to trigger an inflammatory response. TLR2 recognizes LTA and peptidoglycan; TLR4 recognizes LPS. TLR2 induces the production of proinflammatory cytokines (CCL2, IL‐1β/6, and TNF‐α). CD14 is a coreceptor for TLR4 (highly expressed on classical monocytes). CD14/TLR4 sense DAMPs | Increased TLR2 expression is associated with poor outcome, neuronal death, and the accumulation of inflammatory cells, including monocytes. TLR2 requires CD36 to initiate an inflammatory response in ischemia. TLR4 is associated with stroke severity and cytokine/ICAM‐1 levels. TLR4 can activate multiple downstream inflammatory pathways to trigger proinflammatory gene expression | [14, 22, 23, 118, 119, 121, 123, 126, 127, 128] |
| VLA‐4/VCAM‐1 | VLA‐4 is expressed in monocytes. VCAM‐1 is expressed in endothelial cells | Rolling, adhesion, and transmigration of monocytes. Blocking VLA‐4/VCAM‐1 reduces monocyte recruitment to the brain vasculature during infection | VCAM‐1 is elevated from stroke onset to the chronic phase. Soluble VCAM‐1 is associated with short‐term mortality | [17, 130, 131] |
Abbreviations: BBB, blood–brain–barrier; BDNF, brain‐derived neurotrophic factor; BMEC, brain microvascular endothelial cell; CCL, C‐C motif chemokine ligand; CCR, C‐C motif chemokine receptor; CX3CL, C‐X3‐C motif chemokine ligand; CX3CR, C‐X3‐C motif chemokine receptor; CXCL, C‐X‐C motif chemokine ligand; CXCL, C‐X‐C motif chemokine ligand; DAMP, damage‐associated molecular pattern; ECM, extracellular matrix; ICAM, intercellular adhesion molecule‐1; IL, interleukin; JNK, c‐Jun N‐terminal kinase; LFA, lymphocyte function‐associated antigen 1; LPS, lipopolysaccharide; LTA, lipoteichoic acid; Ly6C, lymphocyte antigen 6C; MCAO, middle cerebral artery occlusion; MCP‐1, monocyte chemotactic protein‐1; MIP‐1α, macrophage inflammatory protein‐1 alpha; MMP, matrix metalloproteinase; mRNA, messenger RNA; NF‐κB, nuclear factor‐kappa B; NIHSS, National Institutes of Health Stroke Score; NR4A1, nuclear receptor subfamily 4 group A member 1; P2X4R, purinergic receptor P2X4; PDGF, platelet‐derived growth factor; PSGL‐1, P‐selectin glycoprotein ligand‐1; SDF, stromal cell‐derived factor; TJ, tight junction; TLR, Toll‐like receptor; TNF‐α, tumor necrosis factor‐alpha; VCAM, vascular cell adhesion molecule; VEGF, vascular endothelial growth factor; VLA, very late activation antigen.