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Tregs通过IL-10/STAT3诱导小胶质细胞M2型极化减轻脑出血炎症损伤
Regulatory T cells alleviate intracerebral hemorrhage-induced inflammatory injury in mice by modulating microglia M2 polarization through the IL-10/STAT3 pathway
- 第三军医大学学报 2018年40卷第16期 页码：1461-1468
- 作者机构：
- 作者简介：
- 基金信息：国家自然科学基金面上项目(81371674);国家自然科学基金面上项目(81401505)
DOI：10.16016/j.1000-5404.201802129
中图分类号：收稿：2017-11-20，
纸质出版：2018-08-30
- 稿件说明：
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李秋萌, 张文倩, 谭赢, 等. Tregs通过IL-10/STAT3诱导小胶质细胞M2型极化减轻脑出血炎症损伤[J]. 第三军医大学学报, 2018,40(16):1461-1468.
Qiumeng LI, Wenqian ZHANG, Ying TAN, et al. Regulatory T cells alleviate intracerebral hemorrhage-induced inflammatory injury in mice by modulating microglia M2 polarization through the IL-10/STAT3 pathway[J]. Journal of Third Military Medical University, 2018, 40(16): 1461-1468.
李秋萌, 张文倩, 谭赢, 等. Tregs通过IL-10/STAT3诱导小胶质细胞M2型极化减轻脑出血炎症损伤[J]. 第三军医大学学报, 2018,40(16):1461-1468. DOI： 10.16016/j.1000-5404.201802129.
Qiumeng LI, Wenqian ZHANG, Ying TAN, et al. Regulatory T cells alleviate intracerebral hemorrhage-induced inflammatory injury in mice by modulating microglia M2 polarization through the IL-10/STAT3 pathway[J]. Journal of Third Military Medical University, 2018, 40(16): 1461-1468. DOI： 10.16016/j.1000-5404.201802129.
摘要
Abstract
Objective
2
To investigate the effect of regulatory T cells (Tregs) on inflammatory injury induced by intracerebral hemorrhage (ICH) and explore the molecular mechanism.
Methods
2
Twenty C57BL/6 mice were randomized into 4 equal groups
namely ICH with Tregs treatment group
ICH model group
sham operation group
and sham operation with Tregs treatment group.Mouse models of ICH were established by injecting non-anti-coagulated autologous blood (20 μL) into the basal ganglia
followed 24 h later by injection of autologous Tregs
via
the tail vein (normal saline was injected in ICH model and sham operation groups).The changes in neurological deficit score
brain tissue water content
and hematoma volume were observed in the mice 4 days after ICH.ELISA was used to detect the levels of interleukin-6 (IL-6)
tumor necrosis factor-α (TNF-α
) IL-10
and transforming growth factor-β (TGF-β) in the brain tissues
and PCR was used for detecting the changes in the mRNA expression of the signature genes (CCL3
iNOS
Arg1
and Ym1);immunofluorescence assay was used for detecting the specialized protein markers M1 (CD16/32) and M2 (CD206).We also established a BV2 cells/Tregs transwell co-culture system
in which the same inflammatory cytokines and mRNA expressions of the signature genes were detected; Western blotting was used to detect the protein expression of STAT3
p-STAT3 and TGF-β in the co-culture.
Results
2
In mice with ICH
intravenous delivery of Tregs significantly improved the neurological function
relieved cerebral edema and reduced the hematoma volume (
P
<
0.05);administration of Tregs also significantly lowered the expression levels of IL-6
TNF-α
CCL3
and iNOS and increased the levels of IL-10
TG
F-β
Arg1
and Ym1 in the brain tissues (
P
<
0.05).In the co-culture of Tregs and BV2 cells
the expression levels of IL-6
TNF-α
CCL3
iNOS and p-STAT3 increased and those of IL-10
TGF-β
Arg1
and Ym1 decreased significantly as compared with those in the control group (
P
<
0.05).Neutralization of IL-10 in the co-culture caused significant reductions in the expression levels of p-STAT3 and TGF-β proteins and Arg1 and Ym1 mRNA (
P
<
0.05).
Conclusion
2
Tregs alleviate ICH-induced inflammatory injury in mice possibly by modulating microglia M2 polarization through the IL-10/STAT3 pathway.
关键词
Keywords
references
VAN ASCH C J LUITSE M J RINKEL G J Incidence, case fatality, and functional outcome of intracerebral haemorrhage over time, according to age, sex, and ethnic origin: a systematic review and meta-analysis Lancet Neurol 2010 9 2 167 176 10.1016/S1474-4422(09)70340-0 VAN ASCH C J, LUITSE M J, RINKEL G J, et al . Incidence, case fatality, and functional outcome of intracerebral haemorrhage over time, according to age, sex, and ethnic origin: a systematic review and meta-analysis[J ] . Lancet Neurol, 2010, 9(2): 167-176. DOI: 10.1016/S1474-4422(09)70340-0.
ZHOU M WANG H ZHU J Cause-specific mortality for 240 causes in China during 1990-2013: a systematic subnational analysis for the Global Burden of Disease Study 2013 Lancet 2016 387 10015 251 272 10.1016/S0140-6736(15)00551-6 ZHOU M, WANG H, ZHU J, et al . Cause-specific mortality for 240 causes in China during 1990-2013: a systematic subnational analysis for the Global Burden of Disease Study 2013[J ] . Lancet, 2016, 387(10015): 251-272. DOI: 10.1016/S0140-6736(15)00551-6.
MENDELOW A D GREGSON B A FERNANDES H M Early surgery versus initial conservative treatment in patients with spontaneous supratentorial intracerebral haematomas in the International Surgical Trial in Intracerebral Haemorrhage (STICH): a randomised trial Lancet 2005 365 9457 387 397 10.1016/S0140-6736(05)17826-X MENDELOW A D, GREGSON B A, FERNANDES H M, et al . Early surgery versus initial conservative treatment in patients with spontaneous supratentorial intracerebral haematomas in the International Surgical Trial in Intracerebral Haemorrhage (STICH): a randomised trial[J ] . Lancet, 2005, 365(9457): 387-397. DOI: 10.1016/S0140-6736(05)17826-X.
ARONOWSKI J ZHAO X Molecular pathophysiology of cerebral hemorrhage: secondary brain injury Stroke 2011 42 6 1781 1786 10.1161/STROKEAHA.110.596718 ARONOWSKI J, ZHAO X. Molecular pathophysiology of cerebral hemorrhage: secondary brain injury[J]. Stroke, 2011, 42(6): 1781-1786. DOI: 10.1161/STROKEAHA.110.596718.
KEEP R F HUA Y XI G Intracerebral haemorrhage: mechanisms of injury and therapeutic targets Lancet Neurol 2012 11 8 720 731 10.1016/S1474-4422(12)70104-7 KEEP R F, HUA Y, XI G. Intracerebral haemorrhage: mechanisms of injury and therapeutic targets[J]. Lancet Neurol, 2012, 11(8): 720-731. DOI: 10.1016/S1474-4422(12)70104-7.
ROLLAND W B LEKIC T KRAFFT P R Fingolimod reduces cerebral lymphocyte infiltration in experimental models of rodent intracerebral hemorrhage Exp Neurol 2013 241 45 55 10.1016/j.expneurol.2012.12.009 ROLLAND W B, LEKIC T, KRAFFT P R, et al . Fingolimod reduces cerebral lymphocyte infiltration in experimental models of rodent intracerebral hemorrhage[J ] . Exp Neurol, 2013, 241: 45-55. DOI: 10.1016/j.expneurol.2012.12.009.
SICA A MANTOVANI A Macrophage plasticity and polarization: in vivo veritas J Clin Invest 2012 122 3 787 795 10.1172/JCI59643 SICA A, MANTOVANI A. Macrophage plasticity and polarization: in vivo veritas[J ] . J Clin Invest, 2012, 122(3): 787-795. DOI: 10.1172/JCI59643.
SAKAGUCHI S MIYARA M COSTANTINO C M FOXP3+ regulatory T cells in the human immune system Nat Rev Immunol 2010 10 7 490 500 10.1038/nri2785 SA KAGUCHI S, MIYARA M, COSTANTINO C M, et al . FOXP3+ regulatory T cells in the human immune system[J ] . Nat Rev Immunol, 2010, 10(7): 490-500. DOI: 10.1038/nri2785.
LOWTHER D E HAFLER D A Regulatory T cells in the central nervous system Immunol Rev 2012 248 1 156 169 10.1111/j.1600-065X.2012.01130.x LOWTHER D E, HAFLER D A. Regulatory T cells in the central nervous system[J]. Immunol Rev, 2012, 248(1): 156-169. DOI: 10.1111/j.1600-065X.2012.01130.x.
TIEMESSEN M M JAGGER A L Evans H G CD4+CD25+Foxp3+ regulatory T cells induce alternative activation of human monocytes/macrophages Proc Nat Acad Sci 2007 104 49 19446 19451 10.1073/pnas.0706832104 TIEMESSEN M M, JAGGER A L, Evans H G, et al . CD4+CD25+Foxp3+ regulatory T cells induce alternative activation of human monocytes/macrophages[J ] . Proc Nat Acad Sci, 2007, 104(49): 19446-19451. DOI: 10.1073/pnas.0706832104.
ZHOU K ZHONG Q WANG Y C Regulatory T cells ameliorate intracerebral hemorrhage-induced inflammatory injury by modulating microglia/macrophage polarization through the IL-10/GSK3β/PTEN axis J Cereb Blood Flow Metab 2017 37 3 967 979 10.1177/0271678X16648712 ZHOU K, ZHONG Q, WANG Y C, et al . Regulatory T cells ameliorate intracerebral hemorrhage-induced inflammatory injury by modulating microglia/macrophage polarization through the IL-10/GSK3β/PTEN axis[J ] . J Cereb Blood Flow Metab, 2017, 37(3): 967-979. DOI: 10.1177/0271678X16648712.
FANG H CHEN J LIN S CD36-mediated hematoma absorption following intracerebral hemorrhage: negative regulation by TLR4 signaling J Immunol 2014 192 12 5984 5992 10.4049/jimmunol.1400054 FANG H, CHEN J, LIN S, et al . CD36-mediated hematoma absorption following intracerebral hemorrhage: negative regulation by TLR4 signaling[J ] . J Immunol, 2014, 192(12): 5984-5992. DOI: 10.4049/jimmunol.140 0054.
CLARK W GUNION-RINKER L LESSOV N Citicoline treatment for experimental intracerebral hemorrhage in mice Stroke 1998 29 10 2136 2140 10.1161/01.str.29.10.2136 CLARK W, GUNION-RINKER L, LESSOV N, et al . Citicoline treatment for experimental intracerebral hemorrhage in mice[J ] . Stroke, 1998, 29(10): 2136-2140. DOI: 10.1161/01.str.29.10.2136.
WEIRATHER J HOFMANN U D W BEYERSDORF N Foxp3+ CD4+ T cells improve healing after myocardial infarction by modulating monocyte/macrophage differentiation Circulation Research 2014 115 1 55 67 10.1161/circresaha.115.303895 WEIRATHER J, HOFMANN U D W, BEYERSDORF N, et al . Foxp3+ CD4+ T cells improve healing after myocardial infarction by modulating monocyte/macrophage differentiation[J ] . Circulation Research, 2014, 115(1): 55-67. DOI: 10.1161/circresaha.115.303895.
WANG J DOR S Inflammation after intracerebral hemorrhage J Cereb Blood Flow Metab 2007 27 5 894 908 10.1038/sj.jcbfm.9600403 WANG J, DOR S. Inflammation after intracerebral hemorrhage[J]. J Cereb Blood Flow Metab, 2007, 27(5): 894-908. DOI: 10.1038/sj.jcbfm.9600403.
KIPNIS J AVIDAN H CASPI R R Dual effect of CD4+CD25+ regulatory T cells in neurodegeneration: a dialogue with microglia Proc Natl Acad Sci U S A 2004 101 Suppl 2 14663 14669 10.1073/pnas.0404842101 KIPNIS J, AVIDAN H, CASPI R R, et al . Dual effect of CD4+CD25+ regulatory T cells in neurodegeneration: a dialogue with microglia[J ] .Proc Natl Acad Sci U S A, 2004, 101(Suppl 2): 14663-14669. DOI: 10.1073/pnas.0404842101.
BLASI E MATHIESON B J VARESIO L Selective immortalization of murine macrophages from fresh bone marrow by a raf/myc recombinant murine retrovirus Nature 1985 318 6047 667 670 10.1038/318667a0 BLASI E, MATHIESON B J, VARESIO L, et al . Selective immortalization of murine macrophages from fresh bone marrow by a raf/myc recombinant murine retrovirus[J ] . Nature, 1985, 318(6047): 667-670. DOI: 10.1038/318667a0.
KUMAR A ALVAREZ-CRODA D M STOICA B A Microglial/macrophage polarization dynamics following traumatic brain injury J Neurotrauma 2016 33 19 1732 1750 10.1089/neu.2015.4268 KUMAR A, ALVAREZ-CRODA D M, STOICA B A, et al . Microglial/macrophage polarization dynamics following traumatic brain injury[J ] . J Neurotrauma, 2016, 33(19): 1732-1750. DOI: 10.1089/neu.2015.4268.
MORGANTI J M RIPARIP L K ROSI S Call off the dog(ma): M1/M2 polarization is concurrent following traumatic brain injury PLoS ONE 2016 11 1 e0148001 10.1371/journal.pone.0148001 MORGANTI J M, RIPARIP L K, ROSI S. Call off the dog(ma): M1/M2 polarization is concurrent following traumatic brain injury[J]. PLoS ONE, 2016, 11(1): e0148001. DOI: 10.1371/journal.pone.0148001.
KIM C C NAKAMURA M C HSIEH C L Brain trauma elicits non-canonical macrophage activation states J Neuroinflam 2016 13 1 117 10.1186/s12974-016-0581-z KIM C C, NAKAMURA M C, HSIEH C L. Brain trauma elicits non-canonical macrophage activation states[J]. J Neuroinflam, 2016, 13(1):117. DOI: 10.1186/s12974-016-0581-z.
BARRETT J P HENRY R J VILLAPOL S NOX2 deficiency alters macrophage phenotype through an IL-10/STAT3 dependent mechanism: implications for traumatic brain injury J Neuroinflam 2017 14 1 65 10.1186/s12974-017-0843-4 BARRETT J P, HENRY R J, VILLAPOL S, et al . NOX2 deficiency alters macrophage phenotype through an IL-10/STAT3 dependent mechanism: implications for traumatic brain injury[J ] . J Neuroinflam, 2017, 14(1): 65.DOI: 10.1186/s12974-017-0843-4.
COUPER K N BLOUNT D G RILEY E M IL-10: the master regulator of immunity to infection J Immunol 2008 180 9 5771 5777 10.4049/jimmunol.180.9.5771 COUPER K N, BLOUNT D G, RILEY E M. IL-10: the master regulator of immunity to infection[J]. J Immunol, 2008, 180(9): 5771-5777. DOI: 10.4049/jimmunol.180.9.5771.
CURTALE G MIROLO M RENZI T A Negative regulation of Toll-like receptor 4 signaling by IL-10-dependent microRNA-146b Proc Natl Acad Sci USA 2013 110 28 11499 11504 10.1073/pnas.1219852110 CURTALE G, MIROLO M, RENZI T A, et al . Negative regulation of Toll-like receptor 4 signaling by IL-10-dependent microRNA-146b[J ] . Proc Natl Acad Sci USA, 2013, 110(28): 11499-11504. DOI: 10.1073/pnas.1219852110.
BERG D J KÜHN R RAJEWSKY K Interleukin-10 is a central regulator of the response to LPS in murine models of endotoxic shock and the Shwartzman reaction but not endotoxin tolerance J Clin Invest 1995 96 5 2339 2347 10.1172/JCI118290 BERG D J, KÜHN R, RAJEWSKY K, et al . Interleukin-10 is a central regulator of the response to LPS in murine models of endotoxic shock and the Shwartzman reaction but not endotoxin tolerance[J ] . J Clin Invest, 1995, 96(5): 2339- 2347. DOI: 10.1172/JCI118290.
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