Microglial ER Stress Response via IRE1α Regulates Diet-Induced Metabolic Imbalance and Obesity in MiceStilgenbauer, Chen, Pungi
et alMol Metab (2025)
Abstract: Chronic high-fat diet (HFD) feeding triggers hypothalamic inflammation and systemic metabolic dysfunction associated with endoplasmic reticulum (ER) stress. Glial cells, specifically microglia and astrocytes, are central mediators of hypothalamic inflammation. However, the role of Inositol-Requiring Enzyme 1α (IRE1α), a primary ER stress sensor, in glial cells and its contributions to metabolic dysfunction remains elusive.To investigate the role of IRE1α in microglia in mediating HFD-induced metabolic dysfunction.Using novel conditional knockout mouse models (CX3CR1GFPΔIRE1 and TMEM119ERΔIRE1), we deleted IRE1α in immune cells or exclusively in microglia and studied its impact on metabolic health and hypothalamic transcriptional changes in mice fed with HFD for 16 weeks.Deleting IRE1α in microglia significantly reduced LPS-induced pro-inflammatory cytokine gene expression in vitro. IRE1α deletion in microglia protected male mice from HFD-induced obesity, glucose intolerance, and hypothalamic inflammation, with no metabolic benefits observed in female mice. RNA-sequencing revealed significant transcriptional reprogramming of the hypothalamus, including upregulation of genes related to mitochondrial fatty acid oxidation, metabolic adaptability, and anti-inflammatory responses.Our findings reveal that IRE1α-mediated ER stress response in microglia significantly contributes to hypothalamic inflammation and systemic metabolic dysfunction in response to HFD, particularly in males, demonstrating an important role of microglial ER stress response in diet-induced obesity and metabolic diseases.Copyright © 2025 The Author(s). Published by Elsevier GmbH.. All rights reserved.
Differential Roles of Macrophages and Microglia in Subretinal Fibrosis Secondary to Neovascular Age-Related Macular DegenerationSzczepan, Llorián-Salvador, Yi
et alInvest Ophthalmol Vis Sci (2025) 66 (3), 41
Abstract: To investigate the differential role of infiltrating CCR2+ macrophages and CX3CR1+ microglia in neovascular AMD (nAMD)-mediated subretinal fibrosis.Subretinal fibrosis was induced using the two-stage laser protocol in C57BL/6J or CX3CR1gfp/+ mice. The fibrotic lesion was detected using collagen-1 staining in retinal pigment epithelial /choroidal flatmounts. Infiltrating macrophages and microglial were identified using F4/80, CCR2, and CX3CR1 markers at one, three, six, and 10 days after the second laser. Circulating CCR2+ monocytes were depleted using the MC-21 antibody, whereas CX3CR1+ microglia were depleted using PLX5622. BV2 microglia were treated with TGF-β1 for 96 hours, and their profibrotic potential was examined by quantitative PCR and immunocytochemistry.Subretinal fibrosis lesions developed three days after the second laser, accompanied by persistent CCR2+F4/80+ macrophage and CX3CR1+ cell infiltration. Inflammation in the first three days after the second laser was dominated by filtrating CX3CR1+ cells, and the number increased until day (D) 10 post-second laser. Depletion of CCR2+ monocytes from D5-10 significantly reduced the vascular and fibrotic components of the lesion, while CX3CR1+ cell depletion reduced Isolectin B4+ but not collagen-1+ lesion size. Bone marrow-derived macrophages from D6 and D10 mice expressed significantly higher levels of α-smooth muscle actin (α-SMA) and collagen-1 compared to cells from D1 and D3. TGFβ1 treatment increased TMEM119, CX3CR1, IL1b and iNOS gene expression but did not affect Acta2 and Col1a1 gene expression in BV2 cells.CCR2+ monocytes, but not CX3CR1+ microglia, critically contribute to the development of subretinal fibrosis in nAMD.
Reversing Microglial Polarisation by High Intensity Interval Training: A Novel Approach to Mitigate Inflammatory Responses in Osteoarthritis via Jak2/Stat3 PathwayWang, Gao, Xia
et alImmunology (2025)
Abstract: Osteoarthritis (OA) is associated with inflammatory responses linked to microglial polarisation within the central nervous system. However, exploring therapeutic approaches and their underlying mechanisms remains a direction for future research. The present study investigates the potential of high-intensity interval training (HIIT) to alleviate inflammation and facilitate the shift from M1 to M2 microglial polarisation via the Jak2/Stat3 pathway in an OA rat model. Wistar rats were induced with OA via intra-articular injection of monosodium iodoacetate and subsequently underwent HIIT for six consecutive weeks after a 4-week establishment period. Pain thresholds were measured using the von Frey test. Immunofluorescence detected Tmem119, SP, Glu, c-Fos, and IL-6, while flow cytometry analysed CD68 and CD163 levels. Proteomics compared the protein differences between the OA and HIIT groups. The Jak2/Stat3 pathway was activated in OA rats with C-A1 injections, followed by HIIT and subsequent Western blot analysis of inflammatory cytokines. The results indicated a significant decrease in pain threshold from the third to the tenth week in OA rats, while HIIT was found to increase pain thresholds. HIIT was found to promote M1 to M2 microglial polarisation and downregulate the expression of Tmem119, SP, Glu, c-Fos, and IL-6. Additionally, HIIT was more effective in suppressing Jak2 and Stat3 expression levels compared to OA rats. Activation of the Jak2/Stat3 pathway significantly increased the expression of Glu, c-fos, SP, and IL-6, but HIIT reversed these OA-induced increases. Compared to the OA + C-A1 group, the expression levels of Glu, c-fos, SP, and IL-6 were significantly reduced in the OA + C-A1 + HIIT group. In conclusion, HIIT effectively mitigates OA-induced inflammatory responses by reversing microglial polarisation through the Jak2/Stat3 pathway.© 2025 The Author(s). Immunology published by John Wiley & Sons Ltd.
Star Ribbon预染蛋白Marker蛋白质标记物是生物研究和药物开发的重要组成部分。无论是用于蛋白质电泳还是western blot，我们的预染色蛋白质标记物帮助您快速确定目标蛋白质的分子量或评估转移效率。Fc受体蛋白治疗性抗体的功效取决于Fab片段及其对目标抗原的结合活性，还取决于Fc片段及其与关键Fc受体的相互作用。因此，在抗体工程中候选物必须针对一系列受体进行测试。探索我们的重组Fc受体蛋白质的全面收藏！
膜杰作
Star Staining
