Pancreatic Islet Cells Response to IFNγ Relies on Their Spatial Location within an Islet

Burghgrave, Marine De; Lourenço, Chloé; Berthault, Claire; Aïello, Virginie; Villalba, Adrian; Fouque, Alexis; Diedisheim, Marc; Oshima, Masaya; Scharfmann, Raphaël

doi:10.3390/cells12010113

Cited by 3 publications

(1 citation statement)

References 93 publications

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“…Cytokines and ER stress are reported triggers of PDL1 (also known as CD274) expression in beta cells, which occurs in type 1 diabetes [37]. Non-diabetic beta cells do not express PDL1, unlike beta cells from donors with type 1 diabetes, and the expression levels correlate with higher chemokine expression and immune cell-beta cell interaction [37][38][39]. We found that cytokines induced the expression of PDL1 in islets (Fig.…”

Section: Cb1r Blockade Ameliorates the Atf6 Arm Of The Unfolded Prote...mentioning

confidence: 80%

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

Wreven,

Ruiz de Adana,

Hardivillé

et al. 2024

Diabetologia

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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. Data availability Transcriptomic analysis of sorted human beta cells are from Gene Expression Omnibus database, accession no. GSE121863, available at https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSM3448161. Graphical Abstract

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Section: Cb1r Blockade Ameliorates the Atf6 Arm Of The Unfolded Prote...mentioning

confidence: 80%

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

Wreven,

Ruiz de Adana,

Hardivillé

et al. 2024

Diabetologia

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HOMA-beta independently predicts survival in patients with advanced cancer on treatment with immune checkpoint inhibitors

Watanabe,

Eguchi,

Takamoto

et al. 2024

Front. Endocrinol.

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BackgroundAlthough immune checkpoint inhibitors (ICIs) are effective cancer drugs, ICI-induced diabetes is a rare but a life-threatening adverse event for patients. The deleterious action of ICI on pancreatic beta-cell function is a concern. However, the influence of ICI on insulin synthesis and secretion in patients with cancer without diabetes remains unknown.MethodsThis study included 87 patients diagnosed with advanced cancer. Glucose metabolism markers (HbA1c, HOMA-IR) and indicators of insulin secretory capacity (HOMA-beta, C-peptide) were prospectively evaluated in patients with ICI-treated cancers to determine their association with cancer prognosis.ResultsPatients with overall survival (OS) ≥ 7 months had substantially higher HOMA-beta levels at baseline (p=0.008) and 1 month after ICI administration (p=0.006) compared to those with OS <7 months. The median OS was significantly longer in patients with HOMA-beta ≥ 64.24 (13 months, 95%CI: 5.849–20.151, 37 events) than in those with HOMA-beta < 64.24 (5 months, 95%CI: 3.280–6.720, 50 events) (p=0.013). Further, the median progression-free survival (PFS) was significantly longer in patients with HOMA-beta ≥ 66.43 (4 months, 95%CI: 3.073–4.927, 33 events) than in those with HOMA-beta < 66.43 (2 months, 95%CI: 1.410–2.590, 54 events) (p=0.025). Additionally, multivariable logistic regression analysis revealed that a HOMA-beta value ≥ 64.24 independently predicted longer OS in ICI-treated patients.ConclusionsPre-ICI HOMA-beta level is linked to longer OS in ICI-treated patients. This connection is significant and shows that insulin secretory capacity may predict ICI efficacy.

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Pancreatic β-Cell Identity Change through the Lens of Single-Cell Omics Research

Leenders,

de Koning,

Carlotti

2024

IJMS

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The main hallmark in the development of both type 1 and type 2 diabetes is a decline in functional β-cell mass. This decline is predominantly attributed to β-cell death, although recent findings suggest that the loss of β-cell identity may also contribute to β-cell dysfunction. This phenomenon is characterized by a reduced expression of key markers associated with β-cell identity. This review delves into the insights gained from single-cell omics research specifically focused on β-cell identity. It highlights how single-cell omics based studies have uncovered an unexpected level of heterogeneity among β-cells and have facilitated the identification of distinct β-cell subpopulations through the discovery of cell surface markers, transcriptional regulators, the upregulation of stress-related genes, and alterations in chromatin activity. Furthermore, specific subsets of β-cells have been identified in diabetes, such as displaying an immature, dedifferentiated gene signature, expressing significantly lower insulin mRNA levels, and expressing increased β-cell precursor markers. Additionally, single-cell omics has increased insight into the detrimental effects of diabetes-associated conditions, including endoplasmic reticulum stress, oxidative stress, and inflammation, on β-cell identity. Lastly, this review outlines the factors that may influence the identification of β-cell subpopulations when designing and performing a single-cell omics experiment.

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Pancreatic Islet Cells Response to IFNγ Relies on Their Spatial Location within an Islet

Cited by 3 publications

References 93 publications

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

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

HOMA-beta independently predicts survival in patients with advanced cancer on treatment with immune checkpoint inhibitors

Pancreatic β-Cell Identity Change through the Lens of Single-Cell Omics Research

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