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

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 4

Cxcl1 treatment rescues the glucose intolerance in ΔMyD88Peri mice.

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Cxcl1 treatment rescues the glucose intolerance in ΔMyD88Peri mice. (A) ...
(A) A graphical model of the study’s hypothesis, with Cxcl1 highlighted in green. (B) Cultured neonatal pancreatic pericytes were either treated with LPS (right) or left untreated (left), and their supernatant was collected after 48 hours. Bar diagrams (mean ± SD) showing Cxcl1 protein concentration in the supernatant. n = 5. ***P < 0.005 (unpaired, 2-tailed Student’s t test) compared with the untreated group. Each dot represents a single sample. (C) Bar diagram (mean ± SD) showing the results of qPCR analysis of Cxcl1 transcripts in the indicated pancreatic cell types (as detailed in Figure 1, the average levels in islets were set to 1). n = 3–6. ***P < 0.005 (unpaired, 2-tailed Student’s t test) relative to the islets. Each dot represents a single sample. (D) Bar diagram (mean ± SD) shows qPCR analysis of Cxcl1 transcripts in pancreatic pericytes of ΔMyD88Peri mice (red) and nontransgenic (“non tg”; gray; the average was set to 1) mice. n = 3–6. ***P < 0.005 (unpaired, 2-tailed Student’s t test) compared with nontransgenic mice. Each dot represents a single sample. (E–G) Analyses of ΔMyD88Peri mice treated with recombinant Cxcl1 (rCxcl1; blue), PBS-treated ΔMyD88Peri (red), or PBS-treated nontransgenic (black line and gray bars) 15-week-old mice, 1 week after treatment. (E) Bar diagram (mean ± SD) showing the number of macrophages (MФ; CD45+CD64+ cells) and B cells (CD45+CD19+ cells) in 100 islets. n = 6–10. (F) IPGTT. Shown are the mean (± SEM) blood glucose levels (left) and the AUC (right). n = 7–8. (G) Bar diagrams (mean ± SD) showing expression of indicated genes in isolated islets. n = 4–7. *P < 0.05, ***P < 0.005; NS, not significant (1-way ANOVA with Tukey’s post hoc test). Each dot represents a single sample.