Title :

Pharmaceutical targeting of the cannabinoid type 1 receptor impacts the crosstalk between immune cells and islets to reduce insulitis in humans

Author(s) :

Wreven, Elise [Auteur]
Recherche translationnelle sur le diabète - U 1190 [RTD]
Ruiz De Adana, María Soledad [Auteur]
Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas [CIBERDEM]
Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina = Biomedical Research Institute of Málaga and Nanomedicine Platform [IBIMA Plataforma BIONAND ]
Hardivillé, Stéphan [Auteur]
Unité de Glycobiologie Structurale et Fonctionnelle (UGSF) - UMR 8576
Gmyr, Valery [Auteur]
Recherche translationnelle sur le diabète (RTD) - U1190
Pattou Kerr-Conte, Julie [Auteur]
Recherche translationnelle sur le diabète (RTD) - U1190
Chetboun, Mikael [Auteur]
Recherche translationnelle sur le diabète (RTD) - U1190
Pasquetti, Gianni [Auteur]
Recherche translationnelle sur le diabète (RTD) - U1190
Delalleau, Nathalie [Auteur]
Recherche translationnelle sur le diabète (RTD) - U1190
Thevenet, Julien [Auteur]
Recherche translationnelle sur le diabète (RTD) - U1190
Coddeville, anaïs [Auteur]
Recherche translationnelle sur le diabète (RTD) - U1190
Vallejo Herrera, María José [Auteur]
Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina = Biomedical Research Institute of Málaga and Nanomedicine Platform [IBIMA Plataforma BIONAND ]
Hinden, Liad [Auteur]
The Hebrew University of Jerusalem [HUJ]
Benavides Espínola, Inmaculada Concepción [Auteur]
Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina = Biomedical Research Institute of Málaga and Nanomedicine Platform [IBIMA Plataforma BIONAND ]
Gómez Duro, Mireia [Auteur]
Recherche translationnelle sur le diabète - U 1190 [RTD]
Sanchez Salido, Lourdes [Auteur]
Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina = Biomedical Research Institute of Málaga and Nanomedicine Platform [IBIMA Plataforma BIONAND ]
Linares, Francisca [Auteur]
Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas [CIBERDEM]
Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina = Biomedical Research Institute of Málaga and Nanomedicine Platform [IBIMA Plataforma BIONAND ]
Bermúdez-Silva, Francisco-Javier [Auteur]
Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas [CIBERDEM]
Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina = Biomedical Research Institute of Málaga and Nanomedicine Platform [IBIMA Plataforma BIONAND ]
Tam, Joseph [Auteur]
The Hebrew University of Jerusalem [HUJ]
Bonner, Caroline [Auteur]
Recherche translationnelle sur le diabète (RTD) - U1190
Egan, Josephine M. [Auteur]
Olveira, Gabriel [Auteur]
Universidad de Málaga [Málaga] = University of Málaga [Málaga]
Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas [CIBERDEM]
Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina = Biomedical Research Institute of Málaga and Nanomedicine Platform [IBIMA Plataforma BIONAND ]
Colomo, Natalia [Auteur]
Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas [CIBERDEM]
Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina = Biomedical Research Institute of Málaga and Nanomedicine Platform [IBIMA Plataforma BIONAND ]
Pattou, Francois [Auteur]
Recherche translationnelle sur le diabète (RTD) - U1190
Gonzalez Mariscal, Isabel [Auteur]
Recherche translationnelle sur le diabète (RTD) - U1190
Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas [CIBERDEM]
Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina = Biomedical Research Institute of Málaga and Nanomedicine Platform [IBIMA Plataforma BIONAND ]

Journal title :

Diabetologia

Abbreviated title :

Diabetologia

Publisher :

Springer Verlag

Publication date :

2024-06-12

ISSN :

1432-0428

English keyword(s) :

Cannabinoid receptor
CB1R
Endocannabinoid
Insulitis
Islet of Langerhans
Peripheral CB1R inverse agonist
Type 1 diabetes

HAL domain(s) :

Sciences du Vivant [q-bio]
Chimie/Chimie théorique et/ou physique

English abstract : [en]

Aims/hypothesis Insulitis, a hallmark of inflammation preceding autoimmune type 1 diabetes, leads to the eventual loss of functional beta cells. However, functional beta cells can persist even in the face of continuous ...
Show more >Aims/hypothesis Insulitis, a hallmark of inflammation preceding autoimmune type 1 diabetes, leads to the eventual loss of functional beta cells. However, functional beta cells can persist even in the face of continuous insulitis. Despite advances in immunosuppressive treatments, maintaining functional beta cells to prevent insulitis progression and hyperglycaemia remains a challenge. The cannabinoid type 1 receptor (CB1R), present in immune cells and beta cells, regulates inflammation and beta cell function. Here, we pioneer an ex vivo model mirroring human insulitis to investigate the role of CB1R in this process. Methods CD4+ T lymphocytes were isolated from peripheral blood mononuclear cells (PBMCs) from male and female individuals at the onset of type 1 diabetes and from non-diabetic individuals, RNA was extracted and mRNA expression was analysed by real-time PCR. Single beta cell expression from donors with type 1 diabetes was obtained from data mining. Patient-derived human islets from male and female cadaveric donors were 3D-cultured in solubilised extracellular matrix gel in co-culture with the same donor PBMCs, and incubated with cytokines (IL-1β, TNF-α, IFN-γ) for 24–48 h in the presence of vehicle or increasing concentrations of the CB1R blocker JD-5037. Expression of CNR1 (encoding for CB1R) was ablated using CRISPR/Cas9 technology. Viability, intracellular stress and signalling were assayed by live-cell probing and real-time PCR. The islet function measured as glucose-stimulated insulin secretion was determined in a perifusion system. Infiltration of immune cells into the islets was monitored by microscopy. Non-obese diabetic mice aged 7 weeks were treated for 1 week with JD-5037, then euthanised. Profiling of immune cells infiltrated in the islets was performed by flow cytometry. Results CNR1 expression was upregulated in circulating CD4+ T cells from individuals at type 1 diabetes onset (6.9-fold higher vs healthy individuals) and in sorted islet beta cells from donors with type 1 diabetes (3.6-fold higher vs healthy counterparts). The peripherally restricted CB1R inverse agonist JD-5037 arrested the initiation of insulitis in humans and mice. Mechanistically, CB1R blockade prevented islet NO production and ameliorated the ATF6 arm of the unfolded protein response. Consequently, cyto/chemokine expression decreased in human islets, leading to sustained islet cell viability and function. Conclusions/interpretation These results suggest that CB1R could be an interesting target for type 1 diabetes while highlighting the regulatory mechanisms of insulitis. Moreover, these findings may apply to type 2 diabetes where islet inflammation is also a pathophysiological factor.Show less >

Language :

Anglais

Peer reviewed article :

Oui

Audience :

Internationale

Popular science :

Non

ANR Project :

EGID Diabetes Pole

Administrative institution(s) :

Université de Lille
Inserm
CHU Lille

Collections :

• Recherche translationnelle sur le diabète (RTD) - U1190
• Unité de Glycobiologie Structurale et Fonctionnelle (UGSF) - UMR 8576

Submission date :

2024-06-26T21:31:48Z
2024-09-12T17:38:41Z