Targeting Pancreatic Islet NLRP3 Improves Islet Graft Revascularization

Wrublewsky, Selina; Speer, Thimoteus; Nalbach, Lisa; Boewe, Anne S; Pack, Mandy; Alansary, Dalia; Roma, Letícia Prates; Hoffmann, Markus Daniel Alexander; Schmitt, B.; Weinzierl, Andrea; Menger, Michael D.; Laschke, Matthias W.; Ampofo, Emmanuel

doi:10.2337/db21-0851

Cited by 2 publications

(2 citation statements)

References 62 publications

(6 reference statements)

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“…Several studies have already demonstrated that the inhibition of the nucleotide-binding oligomerization domain (NOD)-like receptor protein (NLRP)3 inflammasome, which is the most studied inflammasome sensor due to its involvement in pathogen-driven and sterile inflammation, improves the endocrine function of islets [ 39 , 40 , 41 , 42 ]. In line with this observation, we have recently shown that downregulation of NLRP3 activity in isolated islets prior to transplantation accelerates their engraftment due to an increased insulin gene expression [ 42 ]. However, whether the inhibition of other inflammasomes also promotes islet transplantation is still not known.…”

Section: Discussionmentioning

confidence: 99%

Absent in Melanoma (AIM)2 Promotes the Outcome of Islet Transplantation by Repressing Ischemia-Induced Interferon (IFN) Signaling

Wrublewsky,

Wilden,

Bickelmann

et al. 2023

Cells

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Clinical islet transplantation is limited by ischemia-induced islet cell death. Recently, it has been reported that the absent in melanoma (AIM)2 inflammasome is upregulated by ischemic cell death due to recognition of aberrant cytoplasmic self-dsDNA. However, it is unknown whether AIM2 determines the outcome of islet transplantation. To investigate this, isolated wild type (WT) and AIM2-deficient (AIM2−/−) islets were exposed to oxygen-glucose deprivation to mimic ischemia, and their viability, endocrine function, and interferon (IFN) signaling were assessed. Moreover, the revascularization and endocrine function of grafted WT and AIM2−/− islets were analyzed in the mouse dorsal skinfold chamber model and the diabetic kidney capsule model. Ischemic WT and AIM2−/− islets did not differ in their viability. However, AIM2−/− islets exhibited a higher protein level of p202, a transcriptional regulator of IFN-β and IFN-γ gene expression. Accordingly, these cytokines were upregulated in AIM2−/− islets, resulting in a suppressed gene expression and secretion of insulin. Moreover, the revascularization of AIM2−/− islet grafts was deteriorated when compared to WT controls. Furthermore, transplantation of AIM2−/− islets in diabetic mice failed to restore physiological blood glucose levels. These findings indicate that AIM2 crucially determines the engraftment and endocrine function of transplanted islets by repressing IFN signaling.

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Section: Discussionmentioning

confidence: 99%

Absent in Melanoma (AIM)2 Promotes the Outcome of Islet Transplantation by Repressing Ischemia-Induced Interferon (IFN) Signaling

Wrublewsky,

Wilden,

Bickelmann

et al. 2023

Cells

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“…An IPGTT was performed on day 28 after cell transplantation under the kidney capsule of mice [ 25 , 28 ]. After 14 h of fasting, the mice were intraperitoneally injected with a 10% glucose (wt/vol.)…”

Section: Methodsmentioning

confidence: 99%

CK2 activity is crucial for proper glucagon expression

Ampofo,

Pack,

Wrublewsky

et al. 2024

Diabetologia

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Aims/hypothesis Protein kinase CK2 acts as a negative regulator of insulin expression in pancreatic beta cells. This action is mainly mediated by phosphorylation of the transcription factor pancreatic and duodenal homeobox protein 1 (PDX1). In pancreatic alpha cells, PDX1 acts in a reciprocal fashion on glucagon (GCG) expression. Therefore, we hypothesised that CK2 might positively regulate GCG expression in pancreatic alpha cells. Methods We suppressed CK2 kinase activity in αTC1 cells by two pharmacological inhibitors and by the CRISPR/Cas9 technique. Subsequently, we analysed GCG expression and secretion by real-time quantitative RT-PCR, western blot, luciferase assay, ELISA and DNA pull-down assays. We additionally studied paracrine effects on GCG secretion in pseudoislets, isolated murine islets and human islets. In vivo, we examined the effect of CK2 inhibition on blood glucose levels by systemic and alpha cell-specific CK2 inhibition. Results We found that CK2 downregulation reduces GCG secretion in the murine alpha cell line αTC1 (e.g. from 1094±124 ng/l to 459±110 ng/l) by the use of the CK2-inhibitor SGC-CK2-1. This was due to a marked decrease in Gcg gene expression through alteration of the binding of paired box protein 6 (PAX6) and transcription factor MafB to the Gcg promoter. The analysis of the underlying mechanisms revealed that both transcription factors are displaced by PDX1. Ex vivo experiments in isolated murine islets and pseudoislets further demonstrated that CK2-mediated reduction in GCG secretion was only slightly affected by the higher insulin secretion after CK2 inhibition. The kidney capsule transplantation model showed the significance of CK2 for GCG expression and secretion in vivo. Finally, CK2 downregulation also reduced the GCG secretion in islets isolated from humans. Conclusions/interpretation These novel findings not only indicate an important function of protein kinase CK2 for proper GCG expression but also demonstrate that CK2 may be a promising target for the development of novel glucose-lowering drugs. Graphical Abstract

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Targeting Pancreatic Islet NLRP3 Improves Islet Graft Revascularization

Cited by 2 publications

References 62 publications

Absent in Melanoma (AIM)2 Promotes the Outcome of Islet Transplantation by Repressing Ischemia-Induced Interferon (IFN) Signaling

Absent in Melanoma (AIM)2 Promotes the Outcome of Islet Transplantation by Repressing Ischemia-Induced Interferon (IFN) Signaling

CK2 activity is crucial for proper glucagon expression

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