Multiple members of the chemokine family play a key role in regulating cell migration in physiological and pathological environments, including (post) embryonic development, immune surveillance, and inflammation. Chemokine CC motif ligand 4 (CCL4), also known as macrophage inflammatory protein 1β (MIP-1β), is a member of the CC chemokine family and is considered to play a potential role in the development and/or progression of some diseases.
Fig.1 Chemokine-receptor interactions.
Introduction to CCL4
The molecular weight of CCL4 is 7.8 kDa, and its gene is located on chromosome 17. Mouse and human CCL4 proteins are synthesized into 92 amino acid precursors. The mature secretory protein of 69 amino acids is produced by peptidase decomposing hydrophobic signal peptide. CCL4 is a symmetrical homodimer, and its main secondary structure elements include a triple-stranded antiparallel β-sheet and an NH2-terminus, followed by a four-residue helix. In general, CCL4 dimers are slender cylindrical. CCL4 has chemotaxis on different types of cells, including macrophages, natural killer cells, monocytes, immature dendritic cells, and coronary artery endothelial cells. Besides, CCL4 can also induce calcium mobilization of natural killer cells, monocytes, leukocytes, vascular smooth muscle cells, and progenitor B cells.
Function of CCL4 Expressed by γδ T Cell
γδ T cells recognize microbial antigens, such as heat shock proteins (in mice) or phosphorylated bacterial metabolites (in humans), and control the integrity of the epithelium. The expression of chemokine receptors is also related to the functional program of γδ T cells. In this regard, the strong expression between CCL4 and its receptor CCR5 is related to the T helper 1 phenotype of γδ T cells expressing human Vγ9Vδ2. The regulation of chemokine receptors and the production of local chemokines play an important role in the localization of γδ T cells under physiological and pathophysiological conditions such as infection, inflammation, and tumor defense.
Role of CCL4 in Human Immunodeficiency Virus-1 (HIV-1) Infected Disease
Recent findings demonstrated that both CCL4 and its receptor CCR5 play diverse roles in the inflammatory events underlying HIV-1 infected diseases. The interaction between dendritic cells (DC) and γδ T lymphocytes represents a network of paracrine and cellular contact interactions, which is very important for the integrated immune response of pathogens. HIV-1 infection significantly affected the number and function of the two cell groups. DC/γδ T cell crosstalk may be the target of the virus-induced immune escape. Studies have found that γδ T lymphocytes are absorbed by HIV-1 infected DCs through CCR5-mediated mechanism, and play a CCL4-mediated control role in virus transmission in DC and susceptible CD4⁺ T lymphocytes.
Fig.2 Role of CCL4-CCR5 in HIV infection. (Brelot, 2018)
Therefore, it is necessary for future experiments and clinical studies to clarify the mechanism of anti-CCL4, including directly blocking CCL4 and/or CCR5, which is expected to be a treatment method for HIV-1 infection.
- Moser, B., Willimann, K. Chemokines: role in inflammation and immune surveillance. Annals of the rheumatic diseases. 2004, 63(suppl 2): 84-89.
- Brelot, A., Chakrabarti, L. A. CCR5 revisited: how mechanisms of HIV entry govern AIDS pathogenesis. Journal of molecular biology. 2018, 430(17): 2557-2589.