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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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 1

Pancreatic pericytes express cytokines in a TLR4/MyD88-dependent manner.

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Pancreatic pericytes express cytokines in a TLR4/MyD88-dependent manner....
(A) A graphical model of the study’s hypothesis, with pericytes highlighted in green. (B) Heatmap showing the relative expression of selected cytokines in macrophages, β cells, and pericytes (originally annotated as “quiescent stellate [qSC]” and “activated stellate [aSC]”), employing published scRNA-seq analysis of islets from healthy human donors (48). (C) Heatmap showing the relative expression of selected cytokines in isolated pericytes and islets, employing a previously published RNA-seq analysis of mouse pancreata (41). (D and E) Bar diagram (mean ± SD) showing the results of qPCR analysis of Il1r1 (D) and Tlr4 (E) transcripts in bulk mouse pancreatic tissues, isolated islets (average set to 1), pancreatic endothelial cells (ECs; PECAM1+), pancreatic immune cells (CD45+), and pancreatic pericytes (purified based on YFP expression from Nkx3-2-Cre;R26-YFP mice). n = 3–6. *P < 0.05, ***P < 0.005 (unpaired, 2-tailed Student’s t test). Each dot represents a single sample. (F) Immunofluorescence analysis of adult mouse pancreatic tissue sections for TLR4 (green), the pericytic marker NG2 (red), insulin (white), and DAPI (blue). The right panel shows a higher magnification of the area framed in the white box on the left panel. Scale bars: 25 μm. (G) Cultured neonatal pancreatic pericytes were either treated with LPS (right) or left untreated (left; the average was set to 1) and harvested after 24 hours. Bar diagrams (mean ± SD) showing the expression levels of genes encoding selected cytokines analyzed by qPCR. n = 5. One representative of 2 independent experiments. ***P < 0.005 (unpaired, 2-tailed Student’s t test) compared with the untreated group. Each dot represents a single sample. (H) Bar diagram (mean ± SD) showing the results of qPCR analysis of Myd88 transcripts in pancreatic pericytes purified from Nkx3-2-Cre;R26-YFP (gray) or Nkx3-2-Cre;Myd88fl/fl;R26-YFP (ΔMyD88Peri; red) mice based on YFP expression. n = 4. ***P < 0.005 (unpaired, 2-tailed Student’s t test) compared with nontransgenic mice. Each dot represents a single sample. (I) RNA-seq analysis of pancreatic pericytes from control YFPPeri (Nkx3-2-Cre;R26-YFP) and YFPΔMyD88Peri (Nkx3-2-Cre;Myd88fl/fl;R26-YFP) 15-week-old mice. Volcano plot analysis showing genes upregulated (orange) and downregulated (green) in YFPΔMyD88Peri pericytes. Selected genes are annotated. n = 3.