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Monocyte Chemotactic Protein-1 Signaling Pathway

Figure 1. Monocyte chemotactic protein-1 signaling pathway.

Monocyte chemotactic protein-1 overview

Chemokines include a large class of cytokine chemotaxis content, monocyte chemotactic protein-1 (MCP-1), also known as chemokine ligand 2 (CCL2), belonging to the chemokine family CC subclass. In the family, MCP-1 is a major chemotactic and activating factor of inflammation-associated cells such as monocytes/macrophages and is capable of inducing expression of chemokine receptor 2 (CCR2) in a variety of cells. When MCP-1 binds to CCR2, it directly activates monocytes and other immune cells, such as memory T lymphocytes and natural killer cells, to promote inflammation. MCP-1 also induces the expression of adhesion molecules and interleukin-1 (IL-1), IL-6, tumor necrosis factor-α (TNF-α) and other by activating various intracellular signal transduction pathways. The factor, which causes basophils and mast cells to release histamine, regulates the phagocytic function and pro-apoptotic effect of mononuclear macrophages, and participates in inflammatory diseases and neovascularization and damage repair. MCP-1 recruits and activates inflammatory cells, and activated macrophages secrete profibrotic factors such as transforming growth factor-β1 (TGF-β1), platelet-derived growth factor (PDGF), and plasma plasminogen activator inhibitors. 1 (PAI-1), matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinase-1 (TIMP-1), induce fibroblasts into differentiate myofibroblasts, which play a role in interstitial fibrosis. In addition to chemotactic mononuclear/macrophage-like inflammation-related cells, MCP-1 also affects T cell proliferation and immune function. MCP-1 activates monocytes/macrophages, activated monocytes/macrophages and secrete IL-12, induces initial CD4+ T cells into differentiate Th1 cells, and Th1 cells produce IL-2, gamma interferon (IFN-γ) and TNFα, thus positive feedback enhances cellular immunity and macrophage function; Th2 cells produce IL-4 and IL-10, inhibit Th1 cell response, and inhibit macrophage activation. Karpus found that MCP-1 can directly activate IL-4 promoter, make IL-4 expressing cells increased, so that naive T cells differentiate into Th2 cells, thereby enhancing the type 2 immune response. In addition, MCP-1 can also affect the differentiation of neutrophils. Recent studies have found that MCP-1 plays an important role in autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, type 1 diabetes, multiple sclerosis and inflammatory bowel disease.

Monocyte chemotactic protein-1 family

Human mcp-1 gene is located on the long arm of chromosome 17 (17q11. 2-q21. 1), it consists of three exons and two introns. This gene encodes a MCP-1 precursor molecule containing 99 amino acids and is modified by shear to become a mature molecule containing 76 amino acids. Two intrachain disulfide bonds are formed between the four cysteines in the MCP-1 mature molecule, and these two adjacent highly conserved disulfide bonds may play an important role in the biological activity of MCP-1. The N-terminus of the MCP-1 molecule binds to the receptor and exerts biological activity, while the MCP-1 mutant the N-terminus can become an inhibitor of MCP-1, thereby blocking the downstream signaling pathway and completely inhibiting MCP-1, so the N-terminus may be its chemotactic functional region. In addition, mutations in certain amino acids such as Lys37, Lys38, Arg24, Tyr28, etc. in MCP-1 molecules may also affect their binding to receptors, causing changes in signaling pathways.

Monocyte chemotactic protein-1 signaling pathway

  1. Monocyte chemotactic protein-1 signaling pathway cascade
    MCP-1 can activate monocyte-injured renal parenchyma and induce the secretion of various cytokines and growth factor by binding to the receptor CCR2, allowing proliferation of epithelial cells, endothelial cells, and vascular smooth muscle cells, resulting in inflammation. The reaction changes to interstitial fibrosis, which ultimately leads to renal interstitial fibrosis. MCP-1 gene transcription require activation or binding of NF-κB and AP-1, thereby activating downstream signal transduction pathways. MCP-1 recruits mononuclear/macrophages and stimulates interstitial fibroblasts, which promote extracellular matrix protein deposition, leading to interstitial fibrosis. MCP-1 up-regulates TGF-β and matrix metalloenzyme inhibitors by increasing lymphocyte infiltration and interaction with fibroblast/fibroblasts (TIMP1), which ultimately leads to fibrosis of the intestinal wall.
  2. Pathway regulation
    The role of MCP-1 in ATH inflammatory response and the distribution and function of VSMCs in ET1-specific ETAR suggest that ET1 may also be another important stimulator of MCP-1 activation in VSMCs during ATH vascular inflammation. The experiment confirmed that ET1 can induce the expression of MCP-1 protein and mRNA in rat VSMCs. BQ123 ETAR inhibitor significantly inhibited this effect of ET1, and inhibition of BQ788 ETBR inhibitor is not obvious, suggesting ET1 induced MCP-1 in VSMCs produce primarily mediated by ETAR on VSMCs. Further, antioxidants NAC, ERK, p38MAPK and NF-κB inhibitors PD98059, SB203580 and PDTC also inhibited the expression of MCP-1 protein and mRNA in VSMCs under ET1 stimulation conditions, suggesting that ROS, ERK, p38MAPK and NF-κB may be involved in ET1-induction VSMCs produce MCP-1 signal transduction pathway. Meanwhile, BQ123 NAC and PD98059 or SB203580 can respectively inhibit the phosphorylation of ERK and p38MAPK in the cytoplasm of VSMCs under ET1 stimulation, further proving that ETAR ROS and MAPK signal molecules (ERK p38MAPK) are important signal molecules in the MCP-1 signal pathway induced by ET1. In summary, vasoactive peptide ET1 can induce MCP-1 production in VSMCs via ROS and MAPK signaling pathways, suggesting that ET1→ETAR→ROS→MAPK→NF-κB→MCP-1 may be involved in the activation of VSMCs during ATH. This will provide a new theoretical basis and therapeutic target for the clinical prevention and treatment of ATH. However, the detailed signal transduction mechanism of this pathway and its relationship with other inflammatory need further study. The study found that in the demyelinating lesions of patients with multiple sclerosis, there are many monocyte-derived macrophages, which secrete inflammatory mediators and promote the progression of MS. As a monocyte chemotactic protein, MCP-1 can up-regulate the expression of monocytes, microglia, and T cells in the brain, cerebrospinal fluid, and blood of MS patients, and induce mononuclear macrophage infiltration of CNS, EAE. Symptoms and degree of inflammation were positively correlated with MCP-1 expression. Experimental studies have shown that electroacupuncture can inhibit the expression of MCP-1 in rat cervical spinal cord, possibly by down-regulating the chemotaxis of MCP-1 on monocytes and interfering with the exudation of activated macrophages and autoreactive T cells. The mononuclear macrophages and T cells infiltrated in the CNS were significantly reduced, thereby alleviating the symptoms of EAE rats and inhibiting the progression of the disease.
  3. Relationship with disease
    Systemic lupus erythematosus
    Many studies have shown that the content of MCP-1 is significantly increased in systemic lupus erythematosus lesions. The specific mechanism has been described above. The clinical use of MCP-1 inhibitors or other methods to reduce MCP-1 content can effectively alleviate systemic lupus erythematosus.
    Type 1 diabetes (T1DM)
    T1DM is an organ-specific autoimmune disease, mainly characterized by dysfunction of glucose metabolism caused by destruction of islet β cells, which is genetically predisposed and can be associated with various acute and chronic complications. High levels of MCP-1 observed during islet inflammation.

References:

  1. Lin J, Kakkar V, Lu X. Impact of MCP-1 in atherosclerosis. Current Pharmaceutical Design. 2013, 20(28)
  2. Bishayi B, Bandyopadhyay D, Majhi A, et al. Effect of exogenous MCP-1 on TLR-2 neutralized murine macrophages and possible mechanisms of CCR-2/TLR-2 and MCP-1 signalling during Staphylococcus aureus infection. Immunobiology. 2015, 220(3):350-362.
  3. Panee J. Monocyte Chemoattractant Protein 1 (MCP-1) in Obesity and Diabetes. Cytokine. 2012, 60(1):1-12.
  4. Deshmane S L, Kremlev S, Amini S, et al. Monocyte chemoattractant protein-1 (MCP-1): an overview. J Interferon Cytokine Res. 2009, 29(6):313-326.
  5. Hildebrand D G, Alexander E, Hörber S, et al. IκBζ is a transcriptional key regulator of CCL2/MCP-1. Journal of Immunology. 2013, 190(9):4812-4820.

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