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Beneficial islet inflammation in health depends on pericytic TLR/MyD88 signaling
Anat Schonblum, … , Ruth Ashery-Padan, Limor Landsman
Anat Schonblum, … , Ruth Ashery-Padan, Limor Landsman
Published June 17, 2024
Citation Information: J Clin Invest. 2024;134(14):e179335. https://doi.org/10.1172/JCI179335.
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Research Article Inflammation Metabolism

Beneficial islet inflammation in health depends on pericytic TLR/MyD88 signaling

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Abstract

While inflammation is beneficial for insulin secretion during homeostasis, its transformation adversely affects β cells and contributes to diabetes. However, the regulation of islet inflammation for maintaining glucose homeostasis remains largely unknown. Here, we identified pericytes as pivotal regulators of islet immune and β cell function in health. Islets and pancreatic pericytes express various cytokines in healthy humans and mice. To interfere with the pericytic inflammatory response, we selectively inhibited the TLR/MyD88 pathway in these cells in transgenic mice. The loss of MyD88 impaired pericytic cytokine production. Furthermore, MyD88-deficient mice exhibited skewed islet inflammation with fewer cells, an impaired macrophage phenotype, and reduced IL-1β production. This aberrant pericyte-orchestrated islet inflammation was associated with β cell dedifferentiation and impaired glucose response. Additionally, we found that Cxcl1, a pericytic MyD88-dependent cytokine, promoted immune IL-1β production. Treatment with either Cxcl1 or IL-1β restored the mature β cell phenotype and glucose response in transgenic mice, suggesting a potential mechanism through which pericytes and immune cells regulate glucose homeostasis. Our study revealed pericyte-orchestrated islet inflammation as a crucial element in glucose regulation, implicating this process as a potential therapeutic target for diabetes.

Authors

Anat Schonblum, Dunia Ali Naser, Shai Ovadia, Mohammed Egbaria, Shani Puyesky, Alona Epshtein, Tomer Wald, Sophia Mercado-Medrez, Ruth Ashery-Padan, Limor Landsman

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Figure 3

Loss of pericytic MyD88 causes β cell dedifferentiation and glucose intolerance.

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Loss of pericytic MyD88 causes β cell dedifferentiation and glucose into...
Fifteen-week-old ΔMyD88Peri (red) and nontransgenic littermates (Cre-negative; ‘‘non tg’’; gray) male mice were analyzed. (A) Graphical model of the study hypothesis, with β cells highlighted in green. (B) Intraperitoneal insulin tolerance test (ITT). The mean (± SEM) blood glucose levels are presented. n = 8–10. (C) Intraperitoneal glucose tolerance test (IPGTT). Shown are mean (± SEM) blood glucose levels (left) and area under the curve (AUC, right). n = 9–12. (D) Bar diagram (mean ± SD) showing the glucose-stimulated insulin secretion (GSIS) of isolated islets. n = 4–5. (E) Bar diagram (mean ± SD) showing the insulin content of the isolated islets. n = 4–5. (F, H, and I) Bar diagrams (mean ± SD) showing β cell gene expression analyzed by qPCR. The average levels in the control islets were set to 1. n = 5–9. (G) Bar diagrams (mean ± SD) showing comparable β cell mass in transgenic and control mice. n = 4. *P < 0.05, **P < 0.01, ***P < 0.005; NS, not significant (unpaired, 2-tailed Student’s t test) compared to control.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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