CCR2-Gene

The CCR2 gene is located in the region of the chemokine receptor gene cluster. The CCR2 gene encodes 2 isoforms of the CCR2 receptor. Its ligand is the chemokine CCL2 (also called monocyte chemoattractant protein-1). Chemokine CCL2 specifically mediates monocyte chemotaxis (Zhao BN et al. 2019). The CCL2/CCR2- chemokine axis is an important component for inflammatory activities of the monocyte/macrophage system (Sozzani S et al. 1997) so also in the severe courses of COVID-19 infection (Chen Y et al. (2020). The CCR2 receptor protein has also long been considered a target for intervention in autoimmune diseases.

However, systemic administration of CCR2 antagonists resulted in a marked increase in CCL2 (Zhao BN et al. 2019). CCL2 is thought to be eliminated from the blood in a CCR2-dependent but G-protein (Gαi, Gαs or Gαq/11)-independent manner. This constitutive internalization occurs rapidly: on a monocyte, the entire cell surface CCR2 population is converted within <30 min.

CCL2 as a CCR2 ligand is involved in monocyte infiltration in inflammatory diseases such as rheumatoid arthritis as well as in the inflammatory response in a tumor parenchyma. Animal studies show that blockade of the CCL2-CCR2 axis greatly reduced tumor incidence by preventing the recruitment of "tumor associated macrophages" (TAMs), thereby potentiating the antitumor efficacy of CD8+ T cells in the tumor microenvironment (Yang H et al. 2020).

CCR2-deficient mice have been shown to take an accelerated Alzheimer's disease-like trajectory compared to wild-type mice. Here, it suggests that immune function and inflammation may be associated with age-related cognitive decline.

Furthermore, the chemokine ligand/receptor axis CCL2/CCR2 appears to play a pathogenetic role in in acute inflammatory demyelinating polyradiculoneuropathy variant Guillain-Barré syndrome (GBS) (Yuan F et al. 2014).

Obesity: In the adipose tissue of CCR2-deficient mice, there is an increased number of eosinophilic leukocytes, greater alternative macrophage activation, and a propensity for type 2 cytokine expression. Moreover, this effect was further enhanced when mice developed nutritive-induced obesity.

Myocardial infarction: CCR2 surface expression on blood monocytes changes in a diurnal manner (it is higher at the beginning of the active phase) and affects monocyte recruitment to tissues, including the heart. When an acute ischemic event occurs during the active phase, monocytes tend to migrate more into infarcted tissues. Excessive monocyte infiltration produces more inflammation and increases the risk of heart failure.

In an observational study of gene expression in blood leukocytes in humans, evidence was found for a relationship between CCR2 expression and cognitive function. Higher CCR2 expression was associated with poorer performance on the MMSE assessment of cognitive function.

1. Chen Y et al. (2020) IP-10 and MCP-1 as biomarkers associated with disease severity of COVID-19. Mol Med 26:97.
2. Sozzani S et al (1997) MCP-1 and CCR2 in HIV infection: regulation of agonist and receptor expression. J Leukoc Biol 62:30-33.
3. Wachira D et al (2015) Chemokine coreceptor-2 gene polymorphisms among HIV-1 Infected Individuals in Kenya. Dis Markers: 952067. doi: 10.1155/2015/952067.
4. Yang H et al. (2020) CCL2-CCR2 axis recruits tumor-associated macrophages to induce immune evasion through PD-1 signaling in esophageal carcinogenesis. Mol Cancer19:41.
5. Yuan F et al. (2014) CCR2 gene deletion and pharmacologic blockade ameliorate a severe murine experimental autoimmune neuritis model of Guillain-Barré syndrome. PLoS One. 9:e90463.
6. Zhao BN et al. (2019) CCR2-Mediated Uptake of Constitutively Produced CCL2: A Mechanism for Regulating Chemokine Levels in the Blood. J Immunol 203:3157-3165.