Dynamic control of proinflammatory cytokines Il-1β and Tnf-α by macrophages in zebrafish spinal cord regeneration

被引：220

作者：

Tsarouchas, Themistoklis M. ^{[1
]}

Wehner, Daniel ^{[1
,4
]}

Cavone, Leonardo ^{[1
]}

Munir, Tahimina ^{[1
]}

Keatinge, Marcus ^{[1
]}

Lambertus, Marvin ^{[1
,5
]}

Underhill, Anna ^{[1
]}

Barrett, Thomas ^{[1
]}

Kassapis, Elias ^{[1
]}

Ogryzko, Nikolay ^{[2
]}

Feng, Yi ^{[2
]}

van Ham, Tjakko J. ^{[3
]}

Becker, Thomas ^{[1
]}

Becker, Catherina G. ^{[1
]}

机构：

[1] Univ Edinburgh, Ctr Discovery Brain Sci, Chancellors Bldg,49 Little France Crescent, Edinburgh EH16 4SB, Midlothian, Scotland

[2] Univ Edinburgh, MRC Ctr Inflammat Res, Queens Med Res Inst, Edinburgh EH16 4TJ, Midlothian, Scotland

[3] Erasmus Univ, Dept Clin Genet, Med Ctr, Wytemaweg 80, NL-3015 CN Rotterdam, Netherlands

[4] Tech Univ Dresden, DFG Ctr Regenerat Therapies Dresden, Fetscherstr 105, D-01307 Dresden, Germany

[5] Univ Oslo, Sch Pharm, Dept Pharmaceut Biosci, N-0316 Oslo, Norway

来源：

NATURE COMMUNICATIONS | 2018年 / 9卷

基金：

英国生物技术与生命科学研究理事会; 英国国家替代、减少和改良动物研究中心;

关键词：

NECROSIS-FACTOR-ALPHA; AXONAL REGENERATION; NEURITE OUTGROWTH; ENDOTHELIAL-CELLS; SECONDARY INJURY; NERVOUS-SYSTEM; EXPRESSION; NEURONS; MODEL; INTERLEUKIN-1-BETA;

D O I：

10.1038/s41467-018-07036-w

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Spinal cord injury leads to a massive response of innate immune cells in non-regenerating mammals, but also in successfully regenerating zebrafish. However, the role of the immune response in successful regeneration is poorly defined. Here we show that inhibiting inflammation reduces and promoting it accelerates axonal regeneration in spinal-lesioned zebrafish larvae. Mutant analyses show that peripheral macrophages, but not neutrophils or microglia, are necessary for repair. Macrophage-less irf8 mutants show prolonged inflammation with elevated levels of Tnf-alpha and Il-1 beta. Inhibiting Tnf-a does not rescue axonal growth in irf8 mutants, but impairs it in wildtype animals, indicating a pro-regenerative role of Tnf-a. In contrast, decreasing Il-1 beta levels or number of Il-1 beta+ neutrophils rescue functional regeneration in irf8 mutants. However, during early regeneration, interference with Il-1 beta function impairs regeneration in irf8 and wildtype animals. Hence, inflammation is dynamically controlled by macrophages to promote functional spinal cord regeneration in zebrafish.

引用

页数：17

共 71 条

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