Abstract
Monocyte chemoattractant protein-1 (MCP-1/CCL2) is renowned for its ability to drive the chemotaxis of myeloid and lymphoid cells. It orchestrates the migration of these cell types both during physiological immune defense and in pathological circumstances, such as autoimmune diseases including rheumatoid arthritis and multiple sclerosis, inflammatory diseases including atherosclerosis, as well as infectious diseases, obesity, diabetes, and various types of cancer. However, new data suggest that the scope of CCL2's functions may extend beyond its original characterization as a chemoattractant. Emerging evidence shows that it can impact leukocyte behavior, influencing adhesion, polarization, effector molecule secretion, autophagy, killing, and survival. The direction of these CCL2-induced responses is context dependent and, in some cases, synergistic with other inflammatory stimuli. The involvement of CCL2 signaling in multiple diseases renders it an interesting therapeutic target, although current targeting strategies have not met early expectations in the clinic. A better understanding of how CCL2 affects immune cells will be pivotal to the improvement of existing therapeutic approaches and the development of new drugs. Here, we provide an overview of the pleiotropic effects of CCL2 signaling on cells of the myeloid lineage, beyond chemotaxis, and highlight how these actions might help to shape immune cell behavior and tumor immunity.
Highlights
Monocyte chemoattractant protein-1 [MCP-1, chemokine nomenclature: C–C motif chemokine ligand 2 (CCL2)] is a member of the chemokine family, a collection of small, secreted, chemotactic cytokines, named after their best known function of attracting cells [1]
CCL2 expression is inducible, triggered upon exposure to inflammatory stimuli, such as interleukin-1, interleukin-4, interleukin-6 (IL-1, IL-4, and IL-6), tumor necrosis factor α (TNFα), transforming growth factor β (TGFβ), lipopolysaccharide (LPS), interferon γ (IFNγ), plateletderived growth factor (PDGF), vascular endothelial growth factor (VEGF), macrophage colonystimulating factor (M-CSF), and granulocyte-macrophage colony-stimulating factor (GM-CSF) [29,30,31,32,33]. It is found in the circulation, where it has been suggested as a diagnostic biomarker of breast cancer and prostate cancer [34, 35], as well as in tissues [36], where it attracts leukocytes to sites of infection or injury to mediate defense and repair
We have summarized how this chemokine influences myeloid cell function and modulates immune responses (Figure 1)
Summary
Monocyte chemoattractant protein-1 [MCP-1, chemokine nomenclature: C–C motif chemokine ligand 2 (CCL2)] is a member of the chemokine family, a collection of small, secreted, chemotactic cytokines, named after their best known function of attracting cells [1]. CCL2 is presented by the endothelium via proteoglycans as a guidance cue for extravasation, which subsequently activates G-protein-coupled receptor-mediated transmigration events In the tissue, it further guides monocytes along a chemokine gradient to the location of insult [135, 136]. At the leukocyte/endothelial interface, CCL2 is not merely acting as guidance cue; it increases firm adhesion of human monocytes to vascular endothelium under flow conditions, monitored via video microscopy [88] This effect was activated in response to endothelially produced CCL2 [89] and mediated by specific monocytic cell surface receptors. It was shown that CCL2 increased monocyte adhesion to TNFα-stimulated human pulmonary artery endothelial cells under flow conditions, in a β2-integrin-dependent manner [89]. Hyperactivates autophagy rCCL2 h CD11b+ cells treated with rCCL2 under serum deprivation
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