Pleiotropic Immune Functions of Chemokine Receptor 6 in Health and Disease

Abstract

C-C chemoattractant cytokine (chemokine) receptor 6 (CCR6) and its exclusive binding molecule CCL20 is an extremely important chemokine receptor-ligand pair which controls cell migration and immune induction during inflammatory disease. Not many scientific studies have been undertaken to study its immune mechanisms in detail, but its unique contribution to steady state cell chemotaxis in upholding immune tolerance and regulating immune homeostasis during inflammation is evident in multiple systems in the human body, including skin, liver, lung, kidney, brain, eye, joints, gonads and the gut. The role of CCR6 is constitutively expressed as a series of much debilitating severe inflammatory and autoimmune diseases, Human Immunodeficiency Virus (HIV) and cancer metastasis. CD4+ T cells, the central organizers of adaptive immunity, are stringently mobilized by the CCR6/CCL20 axis also induced by cytokines and a host of other factors in a carefully executed immune modulation scenario, to bring about a delicate balance between inflammation inducing TH17 cells and regulatory Treg cells. Although the exact immune regulatory role is not elucidated as yet, the CCR6/CCL20 axis is implicated as a front runner which determines the polarization of TH17 and regulatory Treg cells, upon which depends the resolution or progression of many debilitating disorders. This review therefore aims at emphasizing the pleiotropic significance of the chemokines CCR6 and CCL20 in immunologic function in multiple organ systems, thereby hoping to accentuate its value in future therapeutic modalities.

CCR6–CCL20 Axis in IBD: What Have We Learnt in the Last 20 Years?

“…A link between obesity, inflammation and the role of CCR6 in it is demonstrated by recent research work [59]. Excessive mobilization of immune cells and the associated cytokine release causing inflammation in the gut is increased by obesity because the adipose tissue lymphocytes that express CCR6 are attracted towards mature adipocytes which produce significant amounts of CCL20 [9]. CCR6 expressing B cells and γδ T cells are avidly recruited by CCL20 polarized lymphocyte migration to the gut.…”

“…The average cost of managing the disease per annum in Australia alone is in the range of $250,000. Although genetic predisposition plays a critical role with more than 200 susceptibility gene loci being already identified, all age groups from all walks of life are at risk of contracting IBD linked to a host of environmental roles [9][10][11][12]. Additionally, CCR6-CCL20 may have pleiotropic immunological roles in a variety of inflammatory disorders involving the human organs: skin, liver, lung, kidney, brain, eye, joints, gonads and gut, as well as human sperm, human immunodeficiency virus (HIV) and cancer metastasis [9].…”

“…Obesity has been shown to induce IL-6 secretion which enhances the proliferation of tumor-promoting macrophages that release CCL20. Wunderlich et al additionally showed that dietary-induced obesity could leave colitis patients at a higher risk of developing cancer via increased recruitment of inflammatory immune cells to the gut which promotes active inflammation [9,59].…”

“…In summary, the characteristic role of the regulatory Treg cells that express CCR6, that are induced by the cytokines TGF-β, IL-35 and IL-10, is to produce immune suppression in the gut during an inflammatory episode such as colitis [9].…”

CCR6–CCL20-Mediated Immunologic Pathways in Inflammatory Bowel Disease

“…The CCR6-CCL20 axis is a prominent immune modulator in both innate and adaptive immune responses of a wide range of inflammatory diseases. It is associated with tissue damage and injury, human immunodeficiency virus (HIV), ophthalmic disorders, lung and kidney disorders, autoimmune diseases, brain disease, arthrosclerosis, obesity, diabetes, and cancer [1].…”