CXC chemokine receptor 3 (Chemokine_CXCR3)
Type: Family

Chemokines (chemotactic cytokines) are a family of chemoattractant molecules. They attract leukocytes to areas of inflammation and lesions, and play a key role in leukocyte activation. Originally defined as host defense proteins, chemokines are now known to play a much broader biological role . They have a wide range of effects in many different cell types beyond the immune system, including, for example, various cells of the central nervous system , and endothelial cells, where they may act as either angiogenic or angiostatic factors .

The chemokine family is divided into four classes based on the number and spacing of their conserved cysteines: 2 Cys residues may be adjacent (the CC family); separated by an intervening residue (the CXC family); have only one of the first two Cys residues (C chemokines); or contain both cysteines, separated by three intervening residues (CX3C chemokines).

Chemokines exert their effects by binding to rhodopsin-like G protein-coupled receptors on the surface of cells. Following interaction with their specific chemokine ligands, chemokine receptors trigger a flux in intracellular calcium ions, which cause a cellular response, including the onset of chemotaxis. There are over fifty distinct chemokines and least 18 human chemokine receptors . Although the receptors bind only a single class of chemokines, they often bind several members of the same class with high affinity. Chemokine receptors are preferentially expressed on important functional subsets of dendritic cells, monocytes and lymphocytes, including Langerhans cells and T helper cells . Chemokines and their receptors can also be subclassified into homeostatic leukocyte homing molecules (CXCR4, CXCR5, CCR7, CCR9) versus inflammatory/inducible molecules (CXCR1, CXCR2, CXCR3, CCR1-6, CX3CR1).

The CXC chemokine receptors are a subfamily of chemokine receptors that specifically bind and respond to cytokines of the CXC chemokine family. There are currently seven known CXC chemokine receptors in mammals, CXCR1 through to CXCR7.

This entry represents CXCR3, which is expressed in natural killer cells and activated T lymphocytes but not in resting T lymphocytes, B lymphocytes, monocytes or granulocytes . CXCR3 also appears to be constitutively expressed on endothelial cells of medium and large blood vessels . CXCR3 is able to regulate leukocyte trafficking and binding to various chemokines inducing various cellular responses, most notably integrin activation, cytoskeletal changes and chemotactic migration . The main role of CXCR3 is the selective recruitment of effector T cells in both normal tissues and inflammation and it is involved in a number of T cell-mediated inflammatory diseases, such as autoimmune diseases, delayed-type hypersensitivity responses, certain viral diseases and acute transplant rejection . It has been implicated in atherosclerosis , pulmonary fibrosis , type 1 diabetes and nephrotoxic nephritis , and has been implicated in wound healing .

CXCR3 is the receptor for CXCL9 (Mig), CXCL10 (IP10) and CXCL11 (I-TAC), , which are upregulated in response to interferon-gamma and are potent chemoattractants for activated T cells . All three chemokines elicit an increase in intracellular Ca2+ levels and activate phosphoinositide 3-kinase and mitogen-activated protein kinase (MAPK) . CXCR3 is also capable of binding a number of CC chemokines with moderate affinity, including CCL11 (eotaxin), CCL13, CCL20, CCL7, CCL5 . However, it has been reported that CCL11, despite binding with high affinity, may be neither an agonist or an antagonist of the CXCR3 receptor, but sequesters available CCL11 resulting in a lowered response at other receptors .