Chondroitin sulfate proteoglycans prevent immune cell phenotypic conversion and inflammation resolution via TLR4 in rodent models of spinal cord injury.
Chondroitin sulfate proteoglycans prevent immune cell phenotypic conversion and inflammation resolution via TLR4 in rodent models of spinal cord injury.
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硫酸软骨素蛋白聚糖通过TLR4预防脊髓损伤啮齿动物模型中的免疫细胞表型转化和炎症消退。
DOI：
10.1038/s41467-022-30467-5
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发表时间：
2022-05-25
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
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作者：
硫酸软骨素蛋白聚糖（CSPGs）是脊髓损伤后轴突生长和神经可塑性的有效抑制剂。在这里，我们发现CSPGs还通过阻断脊髓损伤啮齿动物模型中促炎免疫细胞向促修复表型的转化，在阻止炎症解决方面发挥关键作用。我们证明了酶消化CSPG糖胺聚糖可以增强免疫细胞的清除率，并在关键的分辨时间点降低促炎蛋白和基因的表达谱。对表型不同的免疫细胞簇的分析显示，CSPGs介导的巨噬细胞和小胶质细胞亚型的调节，以及T淋巴细胞的浸润和组成的变化，表明CSPGs在调节脊髓损伤后的先天和适应性免疫反应中发挥作用。从机制上讲，在促修复免疫细胞中，CSPG激活促炎症表型是TLR4依赖的，这表明TLR4信号是CSPG介导的免疫调节的关键驱动因素。这些研究结果表明，CSPGs是啮齿动物脊髓损伤后炎症消退失败的关键介质，导致炎症病理延长和不可逆的组织破坏。炎症消退失败是脊髓损伤的病理标志。在这里，作者在啮齿动物中表明，硫酸软骨素蛋白多糖通过阻止损伤核心的免疫细胞转化为促溶解表型而导致溶解失败，这是由TLR4介导的。
Chondroitin sulfate proteoglycans (CSPGs) act as potent inhibitors of axonal growth and neuroplasticity after spinal cord injury (SCI). Here we reveal that CSPGs also play a critical role in preventing inflammation resolution by blocking the conversion of pro-inflammatory immune cells to a pro-repair phenotype in rodent models of SCI. We demonstrate that enzymatic digestion of CSPG glycosaminoglycans enhances immune cell clearance and reduces pro-inflammatory protein and gene expression profiles at key resolution time points. Analysis of phenotypically distinct immune cell clusters revealed CSPG-mediated modulation of macrophage and microglial subtypes which, together with T lymphocyte infiltration and composition changes, suggests a role for CSPGs in modulating both innate and adaptive immune responses after SCI. Mechanistically, CSPG activation of a pro-inflammatory phenotype in pro-repair immune cells was found to be TLR4-dependent, identifying TLR4 signalling as a key driver of CSPG-mediated immune modulation. These findings establish CSPGs as critical mediators of inflammation resolution failure after SCI in rodents, which leads to prolonged inflammatory pathology and irreversible tissue destruction. Inflammation resolution failure is a pathological hallmark of spinal cord injury. Here, the authors show in rodents that chondroitin sulfate proteoglycans contribute to failed resolution by preventing immune cells at the injury core from converting to a pro-resolution phenotype, and this is mediated by TLR4.
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影响因子：
9.3
作者：
Dyck S;Kataria H;Alizadeh A;Santhosh KT;Lang B;Silver J;Karimi-Abdolrezaee S
通讯作者：
Karimi-Abdolrezaee S
DOI：
10.1093/brain/awy158
发表时间：
2018-08-01
期刊：
Brain : a journal of neurology
影响因子：
--
作者：
Burnside ER;De Winter F;Didangelos A;James ND;Andreica EC;Layard-Horsfall H;Muir EM;Verhaagen J;Bradbury EJ
通讯作者：
Bradbury EJ
影响因子：
3.9
作者：
Avenoso, Angela;D'Ascola, Angela;Campo, Giuseppe M.
通讯作者：
Campo, Giuseppe M.
影响因子：
32.4
作者：
Buckley, Christopher D.;Gilroy, Derek W.;Serhan, Charles N.
通讯作者：
Serhan, Charles N.
DOI：
10.1007/s00018-020-03656-y
发表时间：
2021-03
期刊：
Cellular and molecular life sciences : CMLS
影响因子：
--
作者：
Ciesielska A;Matyjek M;Kwiatkowska K
通讯作者：
Kwiatkowska K