Microglia endotoxin tolerance is retained after enforced repopulation

IF 8.8 2区医学 Q1 IMMUNOLOGY

Brain, Behavior, and Immunity Pub Date : 2025-04-22 DOI:10.1016/j.bbi.2025.04.014

Tiago Medeiros-Furquim, Anneke Miedema, Edwin Schilder, Nieske Brouwer, Inge R. Holtman, Susanne M. Kooistra, Bart J.L. Eggen

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Abstract

Microglia are crucial for CNS homeostasis and are involved in a wide range of neurodegenerative and neuroinflammatory diseases. Systemic inflammation and infections can contribute to neurodegeneration later in life by affecting microglia. Like other innate immune cells, microglia can develop innate immune memory (IIM) in response to an inflammatory challenge, altering their response to subsequent stimuli. IIM can ameliorate or worsen CNS pathology, but it is unclear if IIM can be reversed to restore microglia functions. Here, we investigated whether microglia depletion-repopulation by inhibition of the colony-stimulating factor 1 receptor with BLZ945 reversed LPS-induced microglia endotoxin tolerance in mice. Repopulated microglia displayed a reduced expression of homeostatic genes and genes related to mitochondrial respiration and TCA cycle metabolism and an increased expression of immune effector and activation genes. Nonetheless, the blunted inflammatory gene response after LPS-preconditioning was retained after a depletion-repopulation cycle. Our study highlights the persistence of endotoxin tolerance in microglia after a depletion-repopulation cycle, which might impact the potential effectiveness of strategies targeted at microglia depletion for clinical applications.

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强制繁殖后小胶质细胞内毒素耐受性保持不变

小胶质细胞对中枢神经系统的稳态至关重要，并广泛参与神经退行性和神经炎症性疾病。全身性炎症和感染可以通过影响小胶质细胞导致以后的神经退行性变。像其他先天免疫细胞一样，小胶质细胞可以在炎症挑战下产生先天免疫记忆（IIM），改变它们对随后刺激的反应。IIM可以改善或恶化中枢神经系统病理，但IIM是否可以逆转以恢复小胶质细胞功能尚不清楚。在这里，我们研究了用BLZ945抑制集落刺激因子1受体是否能逆转lps诱导的小鼠小胶质细胞内毒素耐受性。重新填充的小胶质细胞显示出体内平衡基因和与线粒体呼吸和TCA循环代谢相关的基因的表达减少，免疫效应基因和激活基因的表达增加。尽管如此，lps预处理后的炎症基因反应在耗尽-再生循环后仍保持不变。我们的研究强调了小胶质细胞在消耗-再生周期后内毒素耐受性的持久性，这可能会影响针对小胶质细胞消耗的临床应用策略的潜在有效性。

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来源期刊

Brain, Behavior, and Immunity 医学-免疫学

CiteScore

29.60

自引率

2.00%

发文量

290

审稿时长

28 days

期刊介绍： Established in 1987, Brain, Behavior, and Immunity proudly serves as the official journal of the Psychoneuroimmunology Research Society (PNIRS). This pioneering journal is dedicated to publishing peer-reviewed basic, experimental, and clinical studies that explore the intricate interactions among behavioral, neural, endocrine, and immune systems in both humans and animals. As an international and interdisciplinary platform, Brain, Behavior, and Immunity focuses on original research spanning neuroscience, immunology, integrative physiology, behavioral biology, psychiatry, psychology, and clinical medicine. The journal is inclusive of research conducted at various levels, including molecular, cellular, social, and whole organism perspectives. With a commitment to efficiency, the journal facilitates online submission and review, ensuring timely publication of experimental results. Manuscripts typically undergo peer review and are returned to authors within 30 days of submission. It's worth noting that Brain, Behavior, and Immunity, published eight times a year, does not impose submission fees or page charges, fostering an open and accessible platform for scientific discourse.