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警报素白细胞介素-1α 通过脊髓损伤后的反应性星形胶质细胞和内皮触发继发性变性。

The alarmin interleukin-1α triggers secondary degeneration through reactive astrocytes and endothelium after spinal cord injury.

机构信息

Axe neurosciences du Centre de recherche du Centre hospitalier universitaire (CHU) de Québec-Université Laval et Département de médecine moléculaire de l'Université Laval, Québec, G1V 4G2, QC, Canada.

Institute for Experimental Immunology and Imaging, University Hospital Essen, University of Duisburg-Essen, Essen, D-45141, Germany.

出版信息

Nat Commun. 2022 Oct 2;13(1):5786. doi: 10.1038/s41467-022-33463-x.

DOI:10.1038/s41467-022-33463-x
PMID:36184639
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9527244/
Abstract

Spinal cord injury (SCI) triggers neuroinflammation, and subsequently secondary degeneration and oligodendrocyte (OL) death. We report that the alarmin interleukin (IL)-1α is produced by damaged microglia after SCI. Intra-cisterna magna injection of IL-1α in mice rapidly induces neutrophil infiltration and OL death throughout the spinal cord, mimicking the injury cascade seen in SCI sites. These effects are abolished through co-treatment with the IL-1R1 antagonist anakinra, as well as in IL-1R1-knockout mice which demonstrate enhanced locomotor recovery after SCI. Conditional restoration of IL-1R1 expression in astrocytes or endothelial cells (ECs), but not in OLs or microglia, restores IL-1α-induced effects, while astrocyte- or EC-specific Il1r1 deletion reduces OL loss. Conditioned medium derived from IL-1α-stimulated astrocytes results in toxicity for OLs; further, IL-1α-stimulated astrocytes generate reactive oxygen species (ROS), and blocking ROS production in IL-1α-treated or SCI mice prevented OL loss. Thus, after SCI, microglia release IL-1α, inducing astrocyte- and EC-mediated OL degeneration.

摘要

脊髓损伤 (SCI) 会引发神经炎症，进而导致继发性退化和少突胶质细胞 (OL) 死亡。我们报告称，受损的小胶质细胞在 SCI 后会产生警报素白细胞介素 (IL)-1α。在小鼠的脑脊髓腔中注射 IL-1α 会迅速诱导中性粒细胞浸润和整个脊髓中的 OL 死亡，模拟 SCI 部位所见的损伤级联反应。这些影响可以通过与 IL-1R1 拮抗剂 anakinra 共同治疗或在 IL-1R1 敲除小鼠中消除，后者在 SCI 后表现出运动功能恢复增强。在星形胶质细胞或内皮细胞 (EC) 中条件性恢复 IL-1R1 表达，但不在 OL 或小胶质细胞中恢复，会恢复 IL-1α 诱导的作用，而星形胶质细胞或 EC 特异性 Il1r1 缺失会减少 OL 丢失。由 IL-1α 刺激的星形胶质细胞产生的条件培养基会导致 OL 毒性；此外，IL-1α 刺激的星形胶质细胞会产生活性氧物种 (ROS)，并阻止 IL-1α 处理或 SCI 小鼠中的 ROS 产生可防止 OL 丢失。因此，SCI 后，小胶质细胞释放 IL-1α，诱导星形胶质细胞和 EC 介导的 OL 退化。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/df1a/9527244/a19eb3edc7d1/41467_2022_33463_Fig10_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/df1a/9527244/d47a06d526e3/41467_2022_33463_Fig5_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/df1a/9527244/800723bd03c5/41467_2022_33463_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/df1a/9527244/fe891cdf55f6/41467_2022_33463_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/df1a/9527244/98dba164eac8/41467_2022_33463_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/df1a/9527244/a19eb3edc7d1/41467_2022_33463_Fig10_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/df1a/9527244/50f2ea6031c4/41467_2022_33463_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/df1a/9527244/f5bd113d982f/41467_2022_33463_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/df1a/9527244/39027e5fe4ca/41467_2022_33463_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/df1a/9527244/dfd6dc33355e/41467_2022_33463_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/df1a/9527244/d47a06d526e3/41467_2022_33463_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/df1a/9527244/9bf32dedcbbc/41467_2022_33463_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/df1a/9527244/800723bd03c5/41467_2022_33463_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/df1a/9527244/fe891cdf55f6/41467_2022_33463_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/df1a/9527244/98dba164eac8/41467_2022_33463_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/df1a/9527244/a19eb3edc7d1/41467_2022_33463_Fig10_HTML.jpg

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[6]
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[8]
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本文引用的文献

[1]
Neurotoxic reactive astrocytes induce cell death via saturated lipids.

Nature. 2021-11

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