CCL2

For the ICAO airport code see Candle Lake Airpark, for the diradical compound see Dichlorocarbene.

Chemokine (C-C motif) ligand 2 (CCL2) also known as monocyte chemotactic protein-1 (MCP-1) or small inducible cytokine A2 is a protein that in humans is encoded by the CCL2 gene. CCL2 is a small cytokine belonging to the CC chemokine family. CCL2 recruits monocytes, memory T cells, and dendritic cells to sites of tissue injury, infection, and inflammation.^[1][2]

Genomics

As with many other CC chemokines, CCL2 is located on chromosome 17 (17q11.2-q21.1) in humans.^[3]The gene spans 1,927 bases and lies on the Watson (plus) strand. The gene has three exons and two introns. It is produced as a protein precursor containing signal peptide of 23 amino acids and a mature peptide of 76 amino acids.^[4][5] The predicted weight is 11.025 kiloDaltons (kDa).

In the mouse the homolog is Sig-je.

Population genetics

The levels of this protein vary considerably between normal people. Multivariable-adjusted heritability of CCL2 concentrations in whites of European descent has been reported to be 0.37 in plasma and 0.44 in serum^[6][7]

Molecular biology

It is a monomeric polypeptide, with a molecular weight of approximately 13kDa. It is tethered on endothelial cells by glycosaminoglycan side chains of proteoglycans. It is primarily secreted by monocytes, macrophages and dendritic cells. It is a platelet derived growth factor inducible gene. It is cleaved by the metalloproteinase MMP-12.

The cell surface receptors that bind CCL2 are CCR2 and CCR4.^[8]

This cytokine displays chemotactic activity for monocytes and basophils but not for neutrophils or eosinophils. Deletion of the N-terminal residue converts it from an activator of basophils to an eosinophil chemoattractant. CCL2 causes the degranulation of basophils and mast cells, an effect potentiated by pre-treatment with IL-3 and other cytokines.^[9][10] It augments monocyte anti-tumor activity and is essential for granuloma formation

It is found at the site of tooth eruption and bone degradation. In the bone, CCL2 is expressed by mature osteoclasts and osteoblasts and is under the control of nuclear factor κB (NFκB). In human osteoclasts, it has been shown that CCL2 and RANTES (regulated on activation normal T cell expressed and secreted) are unregulated by RANKL (receptor activator of NFκB ligand). Both MCP-1 and RANTES were also shown to induce the formation of TRAP-positive, multinuclear cells from M-CSF-treated monocytes in the absence of RANKL, but produced osteoclasts that lacked cathepsin K expression and resorptive capacity. It is proposed that CCL2 and RANTES act as autocrine loop in human osteoclast differentiation.^[11]

The CCL2 chemokine is also expressed by neurons, astrocytes and microglia in nervous tissue. Neuronal expression of CCL2 is mainly found in the cerebral cortex, globus pallidus, hippocampus, paraventricular and supraoptic hypothalamic nuclei, lateral hypothalamus, substantia nigra, facial nuclei, motor and spinal trigeminal nuclei, gigantocellular reticular nucleus and in Purkinje cells in the cerebellum.^[12]

Clinical importance

CCL2 has been implicated in the pathogenesis of diseases characterized by monocytic infiltrates, like psoriasis, rheumatoid arthritis and atherosclerosis.^[13]

Administration of anti-CCL2 antibodies in a model of glomerulonephritis have shown reduced macrophage and T cell infiltration, as well as reduced crescent formation, scarring and renal impairment.^[14]

CCL2 is involved in the neuroinflammatory processes that takes place in various central nervous system (CNS) diseases characterized by neuronal degeneration.^[15] Its expression by glial cells is increased in epilepsy,^[16][17] brain ischemia^[11] Alzheimer’s disease^[18] experimental autoimmune encephalomyelitis (EAE),^[19] and traumatic brain injury.^[20]

Hypomethylation of CpG sites in the CCL2 promoter region may be affected by blood glucose and TG, which then increase the serum CCL2 level and may play a role in the vascular complications of type 2 diabetes^[21]

CCL2 induces amylin expression through ERK1/ERK2/JNK-AP1 and NF-κB related signaling pathways independent of CCR2. Amylin upregulation by CCL2 may contribute to elevation of plasma amylin in obesity and insulin resistance.^[22]

Adipocytes secrete various adipokines that may be involved in the negative cross-talk between adipose tissue and skeletal muscle. CCL2 impairs insulin signaling in skeletal muscle cells via ERK1/2 activation at doses similar to its physiological plasma concentrations (200 pg/mL), but does not involve activation of the NF-κB pathway. CCL2 significantly reduced insulin-stimulated glucose uptake in myocytes. CCL2 may represent a molecular link in the negative cross-talk between adipose tissue and skeletal muscle assigning a completely novel important role to CCL2 besides inflammation.^[23]

Incubation of HL-1 cardiomyocytes and human myocytes with oxidized-LDL induced the expression of BNP and CCL2 genes, while native LDL (N-LDL) had no effect.^[24]

Treatment with melatonin in old mice with age related liver inflammation decreased the mRNA expression of TNF-α, IL-1β, HO (HO-1 and HO-2), iNOS, CCL2, NF-κB1, NF-κB2 and NKAP in old male mice. The protein expression of TNF-α, IL-1β was also decreased and IL-10 increased with melatonin treatment. Exogenous administration of melatonin was able to reduce inflammation.^[25]

References

Further reading