What is Chemokine Family?
Chemokines, the small protein-signaling molecules, regulate the migration and activation of various types of leukocytes. Chemokines signal by binding receptors that are members of the seven-transmembrane G-protein coupled family. Through chemokine receptors, chemokines can regulate leukocyte migration, activation, differentiation, and survival during the immune response, and therefore are involved in numerous diseases including inflammation, cancer, and autoimmune disorders. The understanding of the action mechanism of chemokines and their receptors will assist in the rational development of therapeutics that target the chemokine system for better pharmacological profiles.
Chemokine Family is divided into 3 main subfamilies including CXC, CC and CX3C, which based on the arrangement of the conserved cysteine residues.
CXC, a main subfamily of Chemokine Family, has many vital receptors that mediate cell migration to influence multiple biological processes. The CXC chemokine receptor 2 (CXCR2) is mainly expressed on the surface of inflammatory cells and synovial fibroblasts, and also in lung, colon and ovarian cancer cells. Although CXCR2 can be activated by many CXC chemokines, it is mostly activated by CXCL8 (also known as IL-8)， which is essential for neutrophil chemotaxis and angiogenesis in acute and chronic inflammatory conditions. CXCL8 is a member of the ELR+ CXC chemokines, which exhibits a broad range of biological activities. As the CXCR2-CXCL8 complex has critical roles in inflammation and cancer, CXCR2 inhibition has therapeutic potential in conditions such as chronic obstructive pulmonary disease, reperfusion injury and pancreatic cancer.
CC is a main subfamily of Chemokine Family. CCR6 is a CC chemokine receptor that is selectively expressed in immature dendritic cells and memory T-cells. It primarily couples through Gi/o proteins upon activation. CCR6 plays an important role on skin and mucosal surfaces under homeostatic and inflammatory conditions, particularly through the recruitment of proinflammatory IL17-producing T-cells to sites of inflammation. Therefore, CCR6is a potential target for several inflammatory and autoimmune diseases including psoriasis and inflammatory bowel disease.
Fig 1 The diverse activation mechanisms of class A GPCRs
CX3C, one of the Chemokines, regulates many important physiological processes. Fractalkine is one of the CX3C chemokine family, and it is widely expressed in the brain including the hypothalamus. In the brain, fractalkine is expressed in neurons and binds to a CX3C chemokine receptor 1 (CX3CR1) in microglia. The hypothalamus regulates energy homeostasis of which dysregulation is associated with obesity. Therefore, fractalkine-CX3CR1 signaling may be an attractive target for the pharmacological treatment of obesity.
Fig 2 The interaction of CXCL12 and CXCRs
Chemokines are important protein-signaling molecules that regulate various immune responses by activating chemokine receptors. The discovery and understanding of many important target receptors of Chemokine Family will contribute to the development of therapeutics that target the chemokine system.