Proinflammatory signaling in islet β cells propagates invasion of pathogenic immune cells in autoimmune diabetes

Piñeros, Annie R.; Kulkarni, Abhishek; Gao, Hongyu; Orr, Kara S.; Glenn, Lindsey; Huang, Fei; Liu, Yunlong; Gannon, Maureen; Syed, Farooq; Wu, Wenting; Anderson, Cara M.; Evans‐Molina, Carmella; McDuffie, Marcia; Nadler, Jerry L.; Morris, Margaret A.; Mirmira, Raghavendra G.; Tersey, Sarah A.

doi:10.1016/j.celrep.2022.111011

Cited by 18 publications

(20 citation statements)

References 71 publications

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“…It has been shown that inflamed islets cells may limit immune cells activation through PD-L1/PD1 interaction [32,33]. With our experimental model, we confirmed that beta cells express high levels of PD-L1 in inflammatory condition as previously observed [29,49,78]. Interestingly, we demonstrate here that alpha and delta cells also increased Cd274 mRNA, leading to an increase of PD-L1 surface expression confirmed by flow cytometry.…”

Section: Discussionsupporting

confidence: 89%

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

Burghgrave

Lourenço

Berthault

et al. 2022

Cells

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Type 1 diabetes (T1D) is an auto-immune disease characterized by the progressive destruction of insulin-producing pancreatic beta cells. While beta cells are the target of the immune attack, the other islet endocrine cells, namely the alpha and delta cells, can also be affected by the inflammatory milieu. Here, using a flow cytometry-based strategy, we compared the impact of IFNγ, one of the main cytokines involved in T1D, on the three endocrine cell subsets isolated from C57BL/6 mouse islets. RNA-seq analyses revealed that alpha and delta cells exposed in vitro to IFNγ display a transcriptomic profile very similar to that of beta cells, with an increased expression of inflammation key genes such as MHC class I molecules, the CXCL10 chemokine and the programmed death-ligand 1 (PD-L1), three hallmarks of IFNγ signaling. Interestingly, at low IFNγ concentration, we observed two beta cell populations (responders and non-responders) based on PD-L1 protein expression. Our data indicate that this differential sensitivity relies on the location of the cells within the islet rather than on the existence of two different beta cells subsets. The same findings were corroborated by the in vivo analysis of pancreatic islets from the non-obese diabetic mouse model of T1D, showing more intense PD-L1 staining on endocrine cells close to immune infiltrate. Collectively, our work demonstrates that alpha and delta cells are as sensitive as beta cells to IFNγ, and suggests a gradual diffusion of the cytokine into an islet. These observations provide novel insights into the in situ inflammatory processes occurring in T1D progression.

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Section: Discussionsupporting

confidence: 89%

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

Burghgrave

Lourenço

Berthault

et al. 2022

Cells

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“…The effect of HC-5770 to increase PD-L1 levels is likely related to PERK mediated phosphorylation of eIF2α, since we observed that blockade of the p-eIF2α/eIF2B interaction with ISRIB has a similar effect. The role of β cell PD-L1 in dampening the autoimmune attack through its interaction with the receptor PD-1 on immune cells is a highly engaging topic in the context of T1D treatment and islet transplantation, with studies reporting that the PD-L1/PD-1 interaction suppresses the adaptive immune response (55)(56)(57)(58)(59). Conversely, in humans, the use of immune checkpoint inhibitors (which block this interaction) increases the incidence of T1D in genetically susceptible populations (60,61), representing one of the more common immune-related adverse events associated with this therapy.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of the Eukaryotic Initiation Factor-2-α Kinase PERK Decreases Risk of Autoimmune Diabetes in Mice

Muralidharan,

Huang,

Enriquez

et al. 2023

Preprint

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Prevention or delay of autoimmune type 1 diabetes (T1D) onset is possible if molecular triggering events can be pharmacologically targeted. The integrated stress response (ISR) is activated during cellular stress to temporarily halt protein production and redirect energy towards cellular survival. We hypothesized that activity of the ISR in the insulin-producing β cell during T1D becomes maladaptive and renders the cell prone to autoimmunity. We show that suppression of the ISR by using a novel inhibitor of the kinase PERK reverses the translation initiation block in stressed human islets and delays the onset of diabetes, reduces islet inflammation, and preserves β cell mass in T1D-susceptible mice. Single cell RNA sequencing of islets from PERK-inhibited mice shows reductions in the unfolded protein response and PERK signaling pathways as well as alterations in antigen processing and presentation pathways in β cells. Spatial proteomics analysis of islets from these mice show a post-transcriptional increase in the immune checkpoint protein PD-L1 in β cells. Golgi membrane protein 1, whose levels increase following ISR inhibition in human islets and EndoC-βH1 human β cells, interacts with and post-transcriptionally stabilizes PD-L1. Collectively, our studies show that the ISR, mediated by PERK, enhances β cell immunogenicity, and inhibition of PERK may offer a strategy to prevent or delay the development of T1D.

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“…Elimination of this enzyme reduces the influx of pathogenic immune cells into both the pancreatic lymph nodes and islets and increases the entry of more tolerogenic immune cells into the islets. 1 Given that the draining pancreatic lymph node and pancreas are key sites in the initial priming and activity of autoreactive immune cells, respectively, the precise identification and quantitation of immune cells in these two sites are crucial to understanding how the disease process is proceeding and how intervention might alter the process. In this protocol, we focus on the single cell isolation of immune cells from whole pancreas and pancreatic lymph nodes for mass cytometry, or cytometry by time of flight (CyTOF).…”

Section: Before You Beginmentioning

confidence: 99%

Protocol to isolate immune cells from mouse pancreatic lymph nodes and whole pancreas for mass cytometric analyses

et al. 2023

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Proinflammatory signaling in islet β cells propagates invasion of pathogenic immune cells in autoimmune diabetes

Cited by 18 publications

References 71 publications

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

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

Inhibition of the Eukaryotic Initiation Factor-2-α Kinase PERK Decreases Risk of Autoimmune Diabetes in Mice

Protocol to isolate immune cells from mouse pancreatic lymph nodes and whole pancreas for mass cytometric analyses

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