Identification of Novel CCR4 Antagonists Through Inhibition of CCL22-Induced Cell Migration

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Authors
Taheri, Golnar
Keyword
Pain , Transmigration , Antagonist , Chemokine
Abstract
Post-surgical pain (PSP) is a complication of surgical procedures and one of the main contributors to chronic PSP in cases of inadequate management. Thus, PSP management planning is essential to anesthetic and perioperative care to prevent the transition from acute to chronic pain. Concerns about the adverse effects of excessive opioid usage and the risk of drug dependency have led researchers to explore molecular pathways involved in pain development. These investigations shed light on the potential role of inflammatory mediators released by immune cells at the injury site and their impact on sensory neurons, thus contributing to the development and maintenance of pain. In previous studies, our group observed a significant increase in skin-resident dendritic cells (DCs) at the site of injury during the acute stage of inflammation; these DCs secrete the chemokines C-C motif chemokine ligand 22 (CCL22) and C-C motif chemokine ligand 17 (CCL17) which subsequently activate CCR4+ nociceptors to cause pain. This activation results in mechanical and thermal hypersensitivity blocked by C 021, a known CCR4 antagonist. This discovery highlighted CCR4 as a potential target for developing novel analgesic drugs to inhibit the development of acute inflammatory pain. In this study, I investigated 78 potential CCR4 antagonists using an in vitro transmigration assay, focusing on the inhibition of CCL22-mediated migration. RAW 264.7 cell lines, as well as CCR4-transfected HEK293T cells, were used in our studies. Our findings demonstrated increased migration of CCR4+ HEK293T cells towards CCL22, effectively blocked by various concentrations of C 021. We then compared the migration inhibitory characteristics of the 78 compounds at concentrations of 4 and 40 nM of C 021. This led to the identification of two novel CCR4 antagonists with 20% greater efficiency than our control compound C 021. In conclusion, this study introduces two novel CCR4 antagonists that effectively inhibit cellular migration toward CCL22. This provides the initial steps for the development of new, more effective approaches to alleviate post-surgical pain and improve pain management strategies by targeting CCR4.
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