The biological role of CCR4 and its ligands CCL17 and CCL22 in atopic dermatitis: therapeutic implications and future directions

INTRODUCTION: Atopic dermatitis (AD) is a chronic inflammatory skin disorder driven by Th2-related cytokines, including interleukin-4 (IL-4) and IL-13. Recent single-cell sequencing and proteomic studies have demonstrated that sustained immune activity can persist even after treatment with the anti-IL-4 receptor alpha antibody dupilumab. Thus, targeting C-C chemokine receptor 4 (CCR4), which is highly expressed by Th2 cells and drives their migration into the inflamed tissues such as skin in response CCL17 (TARC) and CCL22 (MDC), could be a promising therapeutic approach for the treatment of AD. AREAS COVERED: This review summarizes: 1) the role of CCR4 and its primary endogenous ligands CCL17 and CCL22 in AD pathobiology; 2) the molecular pharmacology and associated signaling pathways of CCR4; and 3) the current landscape of CCR4 inhibitors, including key challenges in their discovery/development. The implications of CCR4 pharmacology in the development of new therapeutic agents are also discussed. EXPERT OPINION: New insights into the function and molecular pharmacology of CCR4 have informed the discovery of molecules that target CCR4 directly (e.g. small-molecule allosteric inhibitors) as well as ones that target the CCL17/CCL22/CCR4 signaling axis broadly (e.g. neutraligands). Ongoing efforts to develop therapies targeting this pathway may yield new treatments for AD.