Retinoic-acid-receptor-related orphan receptor γ (RORγ) is a major transcription factor for proinflammatory IL-17A production. Here, we revealed that the RORγ deficiency protects mice from STZ-induced Type 1 diabetes (T1D) through inhibiting IL-17A production, leading to improved pancreatic islet β cell function, thereby uncovering a potential novel therapeutic target for treating T1D. We further identified a novel RORγ inverse agonist, ginseng-derived panaxadiol, which selectively inhibits RORγ transcriptional activity with a distinct cofactor recruitment profile from known RORγ ligands. Structural and functional studies of receptor-ligand interactions reveal the molecular basis for a unique binding mode for panaxadiol in the RORγ ligand-binding pocket. Despite its inverse agonist activity, panaxadiol induced the C-terminal AF-2 helix of RORγ to adopt a canonical active conformation. Interestingly, panaxadiol ameliorates mice from STZ-induced T1D through inhibiting IL-17A production in a RORγ-dependent manner. This study demonstrates a novel regulatory function of RORγ with linkage of the IL-17A pathway in pancreatic β cells, and provides a valuable molecule for further investigating RORγ functions in treating T1D.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10203104 | PMC |
| http://dx.doi.org/10.1038/s41401-022-01042-x | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
PD-L1-CD80 interactions are required for intracellular signaling necessary for dendritic cell migration.
Sci Adv
January 2025
Department of Medicine, Division of Gastroenterology and Hepatology, University of Colorado School of Medicine, Aurora, CO, USA.
Programmed cell death protein 1 (PD-1) and programmed death ligand 1 (PD-L1) interactions are targets for immunotherapies aimed to reinvigorate T cell function. Recently, it was documented that PD-L1 regulates dendritic cell (DC) migration through intracellular signaling events. In this study, we find that both preclinical murine and clinically available human PD-L1 antibodies limit DC migration.
View Article and Find Full Text PDFNon-saponin from maintains blood-brain barrier integrity by inhibiting NF-κB and p38 MAP kinase signaling pathways to prevent the progression of experimental autoimmune encephalomyelitis.
J Ginseng Res
January 2025
Department of Convergence Medical Science, College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea.
Background: The non-saponin (NS) fraction is an important active component of with multifunctional pharmacological activities including neuroprotective, immune regulatory, anti-inflammatory, and antioxidant effects. However, the effects of NSs on multiple sclerosis (MS), a chronic and autoimmune demyelinating disorder, have not yet been demonstrated.
Purpose: and Methods: The goal of the present study was to demonstrate the pharmacological actions of NSs on movement dysfunctions and the related mechanisms of action using an experimental autoimmune encephalomyelitis (EAE) mouse model of MS.
Development and therapeutic assessment of bispecific nanobodies targeting B-cell activating factor and interleukin-17 for the neutralization of inflammatory mediators in autoimmune diseases.
Int J Biol Macromol
January 2025
School of Life Sciences, Zhengzhou University, Henan, Zhengzhou 450001, China; School of Advanced Agricultural Sciences, Peking University, Beijing 100000, China; Longhu Laboratory, Henan, Zhengzhou 450001, China; Henan Key Laboratory of Immunobiology, Henan, Zhengzhou 450001, China; College of Veterinary Medicine, Henan Agricultural University, Henan, Zhengzhou 450001, China. Electronic address:
Autoimmune diseases are characterized by dysregulated immune responses and chronic inflammation. B cell activating factor (BAFF) and interleukin-17 (IL-17) are key mediators in the pathogenesis of several autoimmune diseases, driving B cell hyperactivation, autoantibody production, and tissue damage. Simultaneous targeting of these pathways may provide a synergistic therapeutic approach.
View Article and Find Full Text PDFCallistephus A from Callistephus chinensis Nees alleviates concanavalin A-induced immunological liver injury in mice by inhibiting the activation of JAK/STAT1 and MAPK signaling pathways.
Int Immunopharmacol
January 2025
School of Functional Food and Wine, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China. Electronic address:
Callistephus chinensis Nees is an herbaceous plant in the Asteraceae family that has various traditional effects, especially in preventing liver disease. Callistephus A (CA) is a sesquiterpene compound with a rare 6/7 ring skeleton, which has been isolated only from the Callistephus chinensis Nees, but whether CA protects the liver is unknown. Immunological liver injury (ILI) is a common liver disease mediated by the immune system.
View Article and Find Full Text PDFExploring the therapeutic potential of Abelmoschi Corolla in psoriasis: Mechanisms of action and inflammatory pathway disruption.
Phytomedicine
January 2025
Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, China; Beijing Institute of Traditional Chinese Medicine, Beijing, China. Electronic address:
Background: Psoriasis is a prevalent chronic inflammatory skin condition for which existing treatments often fall short of fully addressing patient needs. Abelmoschi Corolla (AC), a traditional Chinese medicine, and its ethanol extract, huangkui capsule, are well established for the treatment of chronic kidney diseases. The therapeutic mechanisms of AC include anti-inflammatory effects and immune modulation, which align with psoriasis treatment strategies.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!