Introduction of MCP-1
Monocyte chemotactic protein-1 (MCP-1), also identified as CC chemokine ligand-2 (CCL2), is a compact signaling protein belonging to the chemokine family. Chemokines, ranging in molecular weights from 8 to 14 kDa, are generated by cells of the immune system to govern the movement of other cells in response to chemical signals, a process known as chemotaxis. The chemokine family is divided into four groups, and MCP-1 falls within the CC subgroup, distinguished by the presence of cysteine residues near the N-terminus. In humans, MCP-1 exhibits approximately 60% homology with other MCPs such as MCP-2, MCP-3, and MCP-4.
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MCP-1 holds the distinction of being the initial human CC chemokine to be purified and thoroughly characterized, primarily due to its ability to attract monocytes. Positioned on chromosome 17q11.2-q21.1, MCP-1 is structured with three exons and two introns. Its primary interaction occurs with chemokine receptors, notably CCR2, which plays a pivotal role in mediating its biological effects. The cysteine residues within the amino-terminal domain of CCR2 are essential for the binding of MCP-1, and any mutations in these residues can result in a diminished affinity for MCP-1. Through site-directed mutational analysis, specific regions crucial for MCP-1's biological activity have been identified, specifically amino acids 10-13 and 34-35.
Fig. 1 Structure of MCP-1 (Singh S., et al. 2021).
The Function of MCP-1
MCP-1 orchestrates monocyte chemotaxis through varied signaling pathways like p38 MAPK, Src-kinases, PI3K, and p42/44ERK1/2 MAPKs, with cell-type variations influencing outcomes. Studies indicate p38 MAPK involvement in MCP-1-mediated monocyte relocation. MCP-1 also links intricately to oxidative stress, evident in mice lacking MCP-1 showing reduced oxidative stress. In conditions like acute liver injury, age-related macular degeneration, and diabetes, MCP-1 expression rises in response to oxidative stress, contributing to inflammation and disease progression. MCP-1's role in reactive oxygen species (ROS) production underscores its significance in diverse health conditions. Additionally, MCP-1 deficiency protects against oxidative stress-related damage in various models, emphasizing its pivotal role.
The Role of MCP-1 in Diseases
MCP-1 (Monocyte Chemotactic Protein-1) in Ulcer and Bowel Disease
In the initial stages of inflammation in gastric ulceration, MCP-1 expression is induced by tumor necrosis factor-α (TNF-α), which plays a crucial role in ulcer development. MCP-1 facilitates neutrophil and macrophage infiltration in the interstitial space around the ulcer wound. Helicobacter pylori infection stimulates gastric epithelial cells to release MCP-1, enhancing COX-2 expression in T cells. Ethanol-induced ulcers show increased MCP-1 levels, and treatment reduces MCP-1 levels and inhibits neutrophil recruitment.
In inflammatory bowel disease (IBD), MCP-1 expression is elevated, attracting monocytes to mucosal lesions. IBD patients exhibit higher serum MCP-1 levels than healthy controls, suggesting its involvement in intestinal inflammation. A specific gene polymorphism related to MCP-1 is considered a protective factor for IBD in the European population. In IBD-associated bacterial infections, ELMO1 enhances MCP-1 expression, recruiting and activating monocytes, contributing to bacterial control. Increased MCP-1 levels are observed in irritable bowel syndrome (IBS) patients, further highlighting its role in gastrointestinal diseases.
MCP-1 in Diabetes
MCP-1 plays a key role in insulin resistance, diabetes, and related complications such as nephropathy and retinopathy. Circulating MCP-1 levels significantly increase in type 1 and type 2 diabetes. Adipose tissue-produced MCP-1 induces insulin resistance and macrophage infiltration, contributing to diabetes pathogenesis. MCP-1 polymorphisms are correlated with type 1 diabetes mellitus and its complications. Higher MCP-1 levels are found in diabetic nephropathy patients, serving as a potential biomarker. MCP-1 is associated with renal tubular damage, contributing to diabetic nephropathy progression. In diabetic retinopathy, MCP-1 from retinal neurons activates microglia, implicating its role in disease pathogenesis.
MCP-1 in Cancer
Tumor and stromal cells produce MCP-1, recruiting macrophages to the tumor microenvironment in various cancers. MCP-1 expression is associated with angiogenesis in primary breast tumors. Inflammatory breast cancer overexpresses MCP-1, regulating proteolytic activity and promoting invasion and metastasis. MCP-1 induces invasion, migration, and adhesion of ovarian and prostate cancer cells. MCP-1's role in various cancers suggests its potential as a therapeutic target.
MCP-1 in Respiratory Tract Infection
The participation of MCP-1 in COVID-19 is apparent, as heightened serum levels are linked to the severity of the disease. Several inflammatory mediators, including MCP-1, are implicated in complications arising from COVID-19. Furthermore, increased MCP-1 levels have been identified in individuals with active pulmonary tuberculosis, indicating its involvement in the host's responses to Mycobacterium tuberculosis infection.
MCP-1 in Brain Disorders
MCP-1 assumes a crucial role in neurodegenerative disorders like Parkinson's disease, Alzheimer's disease, and multiple sclerosis. Elevated MCP-1 levels are evident in Alzheimer's disease, correlating with the severity of the condition. In Parkinson's disease, MCP-1 levels are associated with disease progression and non-motor symptoms. The role of MCP-1 in multiple sclerosis exhibits variability, with distinct expression patterns in different subtypes.
MCP-1 in Joint and Bone Disorders
MCP-1 is implicated in osteoarthritis and rheumatoid arthritis, as indicated by heightened levels in synovial fluid. In osteoporosis, serum MCP-1 levels show an inverse correlation with bone mass density, suggesting its potential as a diagnostic marker. The involvement of MCP-1 in bone remodeling and cancer-induced bone pain underscores its significance in joint and bone disorders.
MCP-1 in Endothelial Dysfunction
The role of MCP-1 in endothelial dysfunction within cardiovascular diseases is noteworthy, as it actively contributes to inflammation and atherosclerosis. This chemokine is intricately linked to the renewal of vascular endothelium, promoting angiogenesis, and aiding in collateral formation. Furthermore, there is a potential association between MCP-1 and endothelial dysfunction in the context of COVID-19.
MCP-1 in Liver Diseases
MCP-1 emerges as a key player in various hepatic disorders, encompassing fibrosis, cirrhosis, hepatitis, and liver cancer. Its involvement lies in facilitating the recruitment of inflammatory cells, thereby fostering hepatic fibrosis. Notably, the levels of MCP-1 correlate with the severity of non-alcoholic steatohepatitis. Additionally, MCP-1 plays a pivotal role in liver damage induced by viruses and inflammatory agents, contributing significantly to fibrosis and the development of hepatocarcinogenesis.
In conclusion, MCP-1 plays a crucial role in various pathological conditions, contributing to inflammation, immune responses, and disease progression. Its involvement in COVID-19 and its potential as a diagnostic and prognostic biomarker emphasize its significance in diverse disorders. While therapeutic targeting of the MCP-1/CCL2-CCR2 axis is explored, caution is warranted due to its essential role in immunity and health maintenance.
Reference
- Singh S., et al. MCP-1: Function, regulation, and involvement in disease. International Immunopharmacology. 2021, 101: 107598.
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