Interleukin-4 and interleukin-13 induce different metabolic profiles in microglia and macrophages that relate with divergent outcomes after spinal cord injury.
Interleukin-4 and interleukin-13 induce different metabolic profiles in microglia and macrophages that relate with divergent outcomes after spinal cord injury.
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DOI：
10.7150/thno.65203
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发表时间：
2021
期刊：
影响因子：
12.4
通讯作者：
Lopez-Vales R
中科院分区：
文献类型：
--
作者：
Amo-Aparicio J;Garcia-Garcia J;Francos-Quijorna I;Urpi A;Esteve-Codina A;Gut M;Quintana A;Lopez-Vales R
背景资料：小胶质细胞和巨噬细胞在脊髓损伤（SCI）后采用促炎表型，这被认为有助于继发性组织变性。我们以前报道过，这部分是由于低水平的抗炎细胞因子，如IL-4。由于IL-13和IL-4共享受体，并且两种细胞因子都在体外驱动小胶质细胞和巨噬细胞朝向抗炎表型，因此我们研究了SCI后施用IL-13和IL-4是否会产生有益效果。研究方法：我们在SCI后48小时给小鼠注射重组IL-13或IL-4，并评估其对小胶质细胞和巨噬细胞表型和功能结果的影响。我们还对从用IL-13或IL-4治疗的小鼠的损伤脊髓中分选的巨噬细胞和小胶质细胞进行RNA测序分析，并通过使用Seahorse技术评估这些细胞的代谢状态。结果如下：我们观察到IL-13诱导SCI后小胶质细胞和巨噬细胞中抗炎标志物的表达，但与IL-4相反，它未能介导功能恢复。我们发现这两种细胞因子在SCI后的小胶质细胞和巨噬细胞中诱导不同的基因签名，并且与IL-13相反，IL-4将小胶质细胞和巨噬细胞的代谢从糖酵解转移到氧化磷酸化。通过测量这些细胞的代谢谱进一步证实了这些发现。重要的是，我们还发现，用IL-4或IL-13刺激的巨噬细胞对神经元无害，但当氧化代谢被阻断时，它们变得具有细胞毒性。这表明，从糖酵解到氧化磷酸化的代谢转变是使小胶质细胞和巨噬细胞的细胞毒性反应最小化所必需的。结论：这些结果表明，SCI后小胶质细胞和巨噬细胞的代谢适应性有助于继发性损伤，旨在促进氧化磷酸化的策略可能是一种新的方法，以尽量减少小胶质细胞和巨噬细胞在神经创伤中的有害作用。
Background: Microglia and macrophages adopt a pro-inflammatory phenotype after spinal cord injury (SCI), what is thought to contribute to secondary tissue degeneration. We previously reported that this is due, in part, to the low levels of anti-inflammatory cytokines, such as IL-4. Since IL-13 and IL-4 share receptors and both cytokines drive microglia and macrophages towards an anti-inflammatory phenotype in vitro, here we studied whether administration of IL-13 and IL-4 after SCI leads to beneficial effects. Methods: We injected mice with recombinant IL-13 or IL-4 at 48 h after SCI and assessed their effects on microglia and macrophage phenotype and functional outcomes. We also performed RNA sequencing analysis of macrophages and microglia sorted from the injured spinal cords of mice treated with IL-13 or IL-4 and evaluated the metabolic state of these cells by using Seahorse technology. Results: We observed that IL-13 induced the expression of anti-inflammatory markers in microglia and macrophages after SCI but, in contrast to IL-4, it failed to mediate functional recovery. We found that these two cytokines induced different gene signatures in microglia and macrophages after SCI and that IL-4, in contrast to IL-13, shifted microglia and macrophage metabolism from glycolytic to oxidative phosphorylation. These findings were further confirmed by measuring the metabolic profile of these cells. Importantly, we also revealed that macrophages stimulated with IL-4 or IL-13 are not deleterious to neurons, but they become cytotoxic when oxidative metabolism is blocked. This suggests that the metabolic shift, from glycolysis to oxidative phosphorylation, is required to minimize the cytotoxic responses of microglia and macrophages. Conclusions: These results reveal that the metabolic fitness of microglia and macrophages after SCI contributes to secondary damage and that strategies aimed at boosting oxidative phosphorylation might be a novel approach to minimize the deleterious actions of microglia and macrophages in neurotrauma.
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影响因子：
4.3
作者：
Chen, Wei;Sandoval, Hector;Kloc, Malgorzata
通讯作者：
Kloc, Malgorzata
影响因子：
6.2
作者：
Hines, Dustin J.;Hines, Rochelle M.;Macvicar, Brian A.
通讯作者：
Macvicar, Brian A.
DOI：
10.1084/jem.20142322
发表时间：
2015-03-09
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Jay TR;Miller CM;Cheng PJ;Graham LC;Bemiller S;Broihier ML;Xu G;Margevicius D;Karlo JC;Sousa GL;Cotleur AC;Butovsky O;Bekris L;Staugaitis SM;Leverenz JB;Pimplikar SW;Landreth GE;Howell GR;Ransohoff RM;Lamb BT
通讯作者：
Lamb BT
影响因子：
--
作者：
Amo-Aparicio, Jesus;Martinez-Muriana, Anna;Lopez-Vales, Ruben
通讯作者：
Lopez-Vales, Ruben
DOI：
10.1523/jneurosci.3257-09.2009
发表时间：
2009-10-28
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Kigerl KA;Gensel JC;Ankeny DP;Alexander JK;Donnelly DJ;Popovich PG
通讯作者：
Popovich PG