PMID- 36716676 OWN - NLM STAT- MEDLINE DCOM- 20230214 LR - 20230321 IS - 1096-0023 (Electronic) IS - 1043-4666 (Linking) VI - 163 DP - 2023 Mar TI - Majoon chobchini reinstates PDL-1 expression and blocks dendritic cell -T helper 17 pathogenic axis in rheumatoid arthritis animal model. PG - 156136 LID - S1043-4666(23)00014-5 [pii] LID - 10.1016/j.cyto.2023.156136 [doi] AB - Dendritic cells (DCs) are the critical players in the puzzle of rheumatoid arthritis (RA) disease pathogenesis. Blockade of DC activation has been shown to curtail Th17 cell differentiation and its aberrant function in RA. Recent studies have pointed to the role of the PI3K/AKT signaling axis in the maturation and activation of DCs. However, it is yet to be established how PI3K/AKT inhibition would lead to the abolishment of DC activation and Th17 cell plasticity in RA. Herein, our study decoded whether and how majoon chobchini, an unani compound, abated dendritic cell maturation and regulated the Th17/Treg paradigm in RA. Given our results, majoon chobchini conspicuously restrained MHC II, CD86 expression and, subsequently elevated PDL-1 levels in DCs in-vivo. Of note, inhibition of DC maturation by majoon chobchini, in turn, favoured suppression of the Th17 cell population while driving Treg cell development in adjuvant induced arthritic (AA) rats. Concurrently, majoon chobchini decreased the catabolic effects of IL-17 (Th17 associated cytokine) via a reciprocal increase in IL-10 (Treg associated cytokine) levels in AA rats. Mechanistically, majoon chobchini sustained FoxO1 nuclear localization signaled through dampened PI3K/AKT phosphorylation in-vitro. In concert, PDL-1 expression was heightened in majoon chobchini treated activated DCs that provides a framework for ablation of the DC-Th17 cell pathogenic axis in RA. Notwithstanding, the PI3K inhibitor LY294002 exhibited similar inhibitory effects. In essence, majoon chobchini enhanced PDL-1 expression that abolished DC maturation via regulation of the PI3K/AKT/FoxO1 axis, thereby hindering Th17 differentiation in an animal model of RA. This further warrants a clinical investigation that could validate majoon chobchini as a prospective therapeutic drug in the treatment of RA. CI - Copyright (c) 2023 Elsevier Ltd. All rights reserved. FAU - Samarpita, Snigdha AU - Samarpita S AD - Immunopathology Lab, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore 632 014, Tamil Nadu, India. FAU - Rasool, Mahaboobkhan AU - Rasool M AD - Immunopathology Lab, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore 632 014, Tamil Nadu, India. Electronic address: rasool.m@vit.ac.in. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20230128 PL - England TA - Cytokine JT - Cytokine JID - 9005353 RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.1.- (Phosphatidylinositol 3-Kinases) RN - 0 (Cytokines) SB - IM MH - Rats MH - Animals MH - *Proto-Oncogene Proteins c-akt/metabolism MH - Phosphatidylinositol 3-Kinases/metabolism MH - *Arthritis, Rheumatoid/metabolism MH - Cytokines/metabolism MH - T-Lymphocytes, Regulatory/metabolism MH - Disease Models, Animal MH - Th17 Cells/metabolism MH - Dendritic Cells/metabolism OTO - NOTNLM OT - Dendritic cells OT - Majoon chobchini OT - PI3K-AKT-FoxO1 axis OT - Programmed cell death ligand 1 OT - Rheumatoid arthritis COIS- Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2023/01/31 06:00 MHDA- 2023/02/15 06:00 CRDT- 2023/01/30 18:15 PHST- 2022/09/22 00:00 [received] PHST- 2022/12/08 00:00 [revised] PHST- 2023/01/16 00:00 [accepted] PHST- 2023/01/31 06:00 [pubmed] PHST- 2023/02/15 06:00 [medline] PHST- 2023/01/30 18:15 [entrez] AID - S1043-4666(23)00014-5 [pii] AID - 10.1016/j.cyto.2023.156136 [doi] PST - ppublish SO - Cytokine. 2023 Mar;163:156136. doi: 10.1016/j.cyto.2023.156136. Epub 2023 Jan 28.