Polar functional group-containing glycolipid CD1d ligands modulate cytokine-biasing responses and prevent experimental colitis

• Published in: Scientific reports 2020-09, Vol.10 (1), p.15766, Article 15766
• Main Authors: Inuki, Shinsuke, Hirata, Natsumi, Kashiwabara, Emi, Kishi, Junichiro, Aiba, Toshihiko, Teratani, Toshiaki, Nakamura, Wataru, Kojima, Yoshimi, Maruyama, Toru, Kanai, Takanori, Fujimoto, Yukari
• Format: Article
• Language: English
• Subjects: 631/92/72; 692/308/153; Animals; Antigens, CD1d - metabolism; Colitis, Ulcerative - metabolism; Colitis, Ulcerative - prevention & control; Cytokines - metabolism; Disease Models, Animal; Drug Design; Galactosylceramides - chemistry; Galactosylceramides - metabolism; Galactosylceramides - pharmacology; Glycolipids - metabolism; Humanities and Social Sciences; Ligands; Mice; multidisciplinary; Science; Science (multidisciplinary); Solubility; Structure-Activity Relationship; Water - chemistry
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-020-72280-4

The MHC class I-like molecule CD1d is a nonpolymorphic antigen-presenting glycoprotein, and its ligands include glycolipids, such as α-GalCer. The complexes between CD1d and ligands activate natural killer T cells by T cell receptor recognition, leading to the secretion of various cytokines (IFN-γ, IL-4, IL-17A, etc.). Herein, we report structure–activity relationship studies of α-GalCer derivatives containing various functional groups in their lipid acyl chains. Several derivatives have been identified as potent CD1d ligands displaying higher cytokine induction levels and/or unique cytokine polarization. The studies also indicated that flexibility of the lipid moiety can affect the binding affinity, the total cytokine production level and/or cytokine biasing. Based on our immunological evaluation and investigation of physicochemical properties, we chose bisamide- and Bz amide-containing derivatives 2 and 3 , and evaluated their in vivo efficacy in a DSS-induced model of ulcerative colitis. The derivative 3 that exhibits Th2- and Th17-biasing responses, demonstrated significant protective effects against intestinal inflammation in the DSS-induced model, after a single intraperitoneal injection.