CCL3

Since the CC chemokine macrophage inflammatory protein-1α (MIP-1α/CCL3) was first identified as a macrophage-derived inflammatory mediator, its biological functions have been extensively studied.

Introduction to CCL3

CCL3 is a member of the CC chemokine family. CCL3 cDNA was originally cloned from RAW264.7 mouse macrophages activated by lipopolysaccharide (LPS) as a gene encoding endogenous mediators of inflammation. CCL3 and related CC chemokines (such as CCL4 and CCL5) are classified as inflammatory chemokines because of their ability to induce chemotactic migration of monocyte cell line cells and lymphocytes into inflamed tissues. CCL3 also regulates the proliferation of hematopoietic stem/progenitor cells (HSPC) in bone marrow (BM).

Function of CCL3 Expressed by γδ T Cell

The migration of γδ T lymphocytes into tissues is directly controlled by chemoattractant factors such as chemokines. Therefore, parallel to the pattern of chemokine production, the expression of chemokine receptors is a determinant of lymphocyte trafficking under physiological and inflammatory conditions. Among them, CCL3 was confirmed to be related to the anti-tumor activity of a variety of solid tumor mouse models. At the same time, it also can activate certain cell types, affect the proliferation of hematopoietic cells, and has osteoclast properties in vitro or in vivo. Besides, CCL3 plays an important role in different models of inflammation in vivo.

Fig.1 Function of CCL3 in the leukemic bone marrow microenvironment. (Baba, 2014)

Role of CCL3 in Diseases

• Antiviral Role of CCL3 in Human Immunodeficiency Virus (HIV) Infections

Collective evidence clearly shows that CCL3 plays an important role in host defense and inflammatory pathology after microbial infection due to its strong chemotactic properties. Studies have shown that Vδ1 T cells isolated from HIV-infected patients express CD27, CCR7, and CD161, which are molecules involved in the migration of γδ T cells across the endothelium. These results suggest that Vδ1 lymphocytes play an important role in the control of HIV infection and the defense against opportunistic infections. Among them, the combination of natural killer receptors (NKp30) and Vδ1 T cells induces the production of CCL3 and inhibits HIV replication.

• Pathologic Role of CCL3 in Leukemia

In addition to the inflammatory effect, CCL3 also has a negative regulatory effect on the proliferation of HSPCs. Leukemia is a hematopoietic tumor that originates from tumor transformation of HSPCs and is thought to involve oligoclonal or heteroclonal cells. The expansion of leukemia cells can be caused by a small number of special leukemia cells called leukemia initiation cells (LICs). Besides, LICs showed similar phenotypes to normal HSPCs, such as self-renewal and cell rest. Therefore, CCL3, which has biological activity in normal HSPC function, may also participate in the occurrence of leukemia. The pathophysiological effects of endogenous media such as CCL3 may lead to the development of new anti-leukemia therapy, which can be used as a supplement for molecular targeted therapy.

Reference

1. Baba, T., Mukaida, N. Role of macrophage inflammatory protein (MIP)-1α/CCL3 in leukemogenesis. Molecular & cellular oncology. 2014, 1(1): 29899.