High mobility group box-1 (HMGB1) is increased in injured mouse spinal cord and can elicit neurotoxic inflammation.
High mobility group box-1 (HMGB1) is increased in injured mouse spinal cord and can elicit neurotoxic inflammation.
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DOI：
10.1016/j.bbi.2017.11.018
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发表时间：
2018-08
期刊：
影响因子：
--
通讯作者：
Popovich PG
中科院分区：
文献类型：
--
作者：
Kigerl KA;Lai W;Wallace LM;Yang H;Popovich PG
炎症是脊髓损伤（SCI）的普遍存在但知之甚少的后果。控制这种反应的机制尚不清楚，但最终会依次激活驻留和募集的免疫细胞。总的来说，这些细胞可以对细胞存活和组织修复发挥不同的作用。HMGB 1是一种广泛表达的DNA结合蛋白，也是一种强有力的炎症刺激物。坏死细胞释放HGMB 1，但HMGB 1也由炎性巨噬细胞主动分泌。本研究的目的是量化HMGB 1在实验性SCI的对照小鼠模型中表达的时空模式，然后确定HMGB 1对SCI后神经炎症和功能恢复的影响。我们记录了SCI诱导的HMGB 1在SCI后各种细胞类型中的细胞核和细胞质分布的变化。这些数据揭示了HMGB 1 mRNA和蛋白质的时间依赖性增加，其中蛋白质在损伤后24-72小时达到最高水平，然后在SCI后14-28天向基线下降。虽然大多数细胞表达核HMGB 1，但在CNS巨噬细胞亚群中发现核标记减少，胞质表达增加，表明这些细胞开始在损伤部位分泌HMGB 1。体外数据表明，细胞外HMGB 1有助于促进具有神经毒性表型的巨噬细胞的发育。在体内证实了HMGB 1引起神经毒性巨噬细胞功能的能力;将500 ng重组HMGB 1注射到完整的脊髓腹角后72小时，炎性CNS巨噬细胞与神经元杀伤的焦点区域共定位。然而，试图通过用中和抗体阻断HMGB 1来赋予SCI后的神经保护是不成功的。总的来说，这些数据暗示HMGB 1是SCI后炎症的新调节剂，并表明HMGB 1的抑制可能是SCI后的新治疗靶点。未来的研究将需要确定更好的方法，以提供最佳浓度的HMGB 1拮抗剂受伤的脊髓。
Inflammation is a ubiquitous but poorly understood consequence of spinal cord injury (SCI). The mechanisms controlling this response are unclear but culminate in the sequential activation of resident and recruited immune cells. Collectively, these cells can exert divergent effects on cell survival and tissue repair. HMGB1 is a ubiquitously expressed DNA binding protein and also a potent inflammatory stimulus. Necrotic cells release HGMB1, but HMGB1 also is actively secreted by inflammatory macrophages. A goal of this study was to quantify spatio-temporal patterns of cellular HMGB1 expression in a controlled mouse model of experimental SCI then determine the effects of HMGB1 on post-SCI neuroinflammation and recovery of function. We documented SCI-induced changes in nuclear and cytoplasmic distribution of HMGB1 in various cell types after SCI. The data reveal a time-dependent increase in HMGB1 mRNA and protein with protein reaching maximal levels 24–72 hours post-injury then declining toward baseline 14–28 days post-SCI. Although most cells expressed nuclear HMGB1, reduced nuclear labeling with increased cytoplasmic expression was found in a subset of CNS macrophages suggesting that those cells begin to secrete HMGB1 at the injury site. In vitro data indicate that extracelluar HMGB1 helps promote the development of macrophages with a neurotoxic phenotype. The ability of HMGB1 to elicit neurotoxic macrophage functions was confirmed in vivo; 72h after injecting 500ng of recombinant HMGB1 into intact spinal cord ventral horn, inflammatory CNS macrophages co-localized with focal areas of neuronal killing. However, attempts to confer neuroprotection after SCI by blocking HMGB1 with a neutralizing antibody were unsuccessful. Collectively, these data implicate HMGB1 as a novel regulator of post-SCI inflammation and suggest that inhibition of HMGB1 could be a novel therapeutic target after SCI. Future studies will need to identify better methods to deliver optimal concentrations of HMGB1 antagonists to the injured spinal cord.
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影响因子：
15.3
作者：
Brambilla, R;Bracchi-Ricard, V;Hu, WH;Frydel, B;Bramwell, A;Karmally, S;Green, EJ;Bethea, JR
通讯作者：
Bethea, JR
影响因子：
8.8
作者：
Gao, Q.;Ma, L. L.;Yin, D. P.
通讯作者：
Yin, D. P.
影响因子：
4.8
作者：
Huttunen, HJ;Fages, C;Rauvala, H
通讯作者：
Rauvala, H
影响因子：
4.7
作者：
Brambilla R;Hurtado A;Persaud T;Esham K;Pearse DD;Oudega M;Bethea JR
通讯作者：
Bethea JR
DOI：
10.1523/jneurosci.3992-08.2009
发表时间：
2009-03-25
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Gensel JC;Nakamura S;Guan Z;van Rooijen N;Ankeny DP;Popovich PG
通讯作者：
Popovich PG