Regulatory T cells exhibit neuroprotective effect in a mouse model of traumatic brain injury Retraction in /10.3892/mmr.2017.6299

Yu,Yunhu; Cao,Fang; Ran,Qishan; Sun,Xiaochuan

doi:10.3892/mmr.2016.5954

Regulatory T cells exhibit neuroprotective effect in a mouse model of traumatic brain injury

Retraction in: /10.3892/mmr.2017.6299

Authors:
- Yunhu Yu
- Fang Cao
- Qishan Ran
- Xiaochuan Sun
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Affiliations: Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China, Department of Cerebrovascular Disease, The First Affiliated Hospital of Zunyi Medical College, Zunyi, Guizhou 563000, P.R. China, Department of Neurosurgery, The Third Affiliated Hospital of Zunyi Medical College, Zunyi, Guizhou 563000, P.R. China
Published online on: November 18, 2016 https://doi.org/10.3892/mmr.2016.5954
Pages: 5556-5566
Copyright: © Yu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Traumatic brain injury (TBI) is a major health and socioeconomic problem as it is associated with high rates of mortality and morbidity worldwide. Regulatory T cells (Tregs) have been reported to reduce inflammatory response in several diseases, including myasthenia gravis, viral myocarditis and cerebral infarction. The present study investigated the role of Tregs in mediating neuro‑protective effects in a mouse model of TBI. Initially, Treg levels were determined, and compared between the controlled cortical impact (CCI) model for moderate TBI and the sham group, by using flow cytometry and ELISA. Afterwards, the number of Tregs was upregulated (by injection) and downregulated (by depletion), respectively, to elucidate the effect of Tregs in the presence of an inflammatory reaction and a deficient neurological function and consequently, in the prognosis of TBI in the mouse. The expression of pro‑inflammatory cytokines [tumor necrosis factor (TNF)‑α, interleukin (IL)‑1β, IL‑6)] and anti‑inflammatory cytokines [IL‑10, transforming growth factor (TGF)‑β] in blood and brain tissues was also measured in the five groups: Μice receiving a saline injection, mice experiencing Treg depletion, small‑dose (SD Tregs, 1.25x105), and mice receiving different doses of Tregs: Moderate‑dose (MD Tregs, 2.5x105) and large‑dose (LD Tregs, 5x105), using ELISA and PCR. Co‑cultures of Tregs and microglia were performed to evaluate the expression of pro‑inflammatory cytokines and observe the interaction between the two types of cells. The regulation patterns in JNK‑NF‑κB pathway by Tregs were also evaluated by western blot analysis. Treg levels were significantly reduced in TBI mouse group on the 3rd day after TBI (P<0.05). In the mouse model of TBI, the expression of pro‑inflammatory cytokines (TNF‑α, IL‑1β, IL‑6) was enhanced, while the expression of anti‑inflammatory cytokines (IL‑10, TGF‑β) was reduced (P<0.05). Tregs exhibited a suppressive effect on inflammatory reactions. In the MD group, the activation of microglia cells was markedly inhibited, compared to the activation in SD and LD groups. The expression of ERK1/2, JNK1/2/3 and NK‑κB was significantly downregulated in the MD group. The results indicated that Tregs exhibited significant neuro‑protective effects, suppressing pro‑inflammatory responses and promoting tissue repair after TBI injury in the mouse, specifically by deactivating the JNK‑NF‑κB pathway. The results of the study show that Tregs potentially participates in neuro‑therapeutic approaches for TBI.

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1	Brasure M, Lamberty GJ, Sayer NA, Nelson NW, Macdonald R, Ouellette J and Wilt TJ: Participation after multidisciplinary rehabilitation for moderate to severe traumatic brain injury in adults: a systematic review. Arch Phys Med Rehabil. 94:1398–1420. 2013. View Article : Google Scholar : PubMed/NCBI
2	Faden AI: Microglial activation and traumatic brain injury. Ann Neurol. 70:345–346. 2011. View Article : Google Scholar : PubMed/NCBI
3	Whalen MJ, Carlos TM, Wisniewski SR, Clark RS, Mellick JA, Marion DW and Kochanek PM: Effect of neutropenia and granulocyte colony stimulating factor-induced neutrophilia on blood-brain barrier permeability and brain edema after traumatic brain injury in rats. Crit Care Med. 28:3710–3717. 2000. View Article : Google Scholar : PubMed/NCBI
4	Ahn MJ, Sherwood ER, Prough DS, Lin CY and DeWitt DS: The effects of traumatic brain injury on cerebral blood flow and brain tissue nitric oxide levels and cytokine expression. J Neurotrauma. 21:1431–1442. 2004. View Article : Google Scholar : PubMed/NCBI
5	Readnower RD, Chavko M, Adeeb S, Conroy MD, Pauly JR, McCarron RM and Sullivan PG: Increase in blood-brain barrier permeability, oxidative stress, and activated microglia in a rat model of blast-induced traumatic brain injury. J Neurosci Res. 88:3530–3539. 2010. View Article : Google Scholar : PubMed/NCBI
6	Liesz A, Suri-Payer E, Veltkamp C, Doerr H, Sommer C, Rivest S, Giese T and Veltkamp R: Regulatory T cells are key cerebroprotective immunomodulators in acute experimental stroke. Nat Med. 15:192–199. 2009. View Article : Google Scholar : PubMed/NCBI
7	Ishibashi S, Maric D, Mou Y, Ohtani R, Ruetzler C and Hallenbeck JM: Mucosal tolerance to E-selectin promotes the survival of newly generated neuroblasts via regulatory T-cell induction after stroke in spontaneously hypertensive rats. J Cereb Blood Flow Metab. 29:606–620. 2009. View Article : Google Scholar : PubMed/NCBI
8	Shi Y, Fukuoka M, Li G, Liu Y, Chen M, Konviser M, Chen X, Opavsky MA and Liu PP: Regulatory T cells protect mice against coxsackievirus-induced myocarditis through the transforming growth factor β-coxsackie-adenovirus receptor pathway. Circulation. 121:2624–2634. 2010. View Article : Google Scholar : PubMed/NCBI
9	Strisciuglio C and van Deventer S: Regulatory T cells as potential targets for immunotherapy in inflammatory bowel disease. Immunotherapy. 2:749–752. 2010. View Article : Google Scholar : PubMed/NCBI
10	Liu R, Zhou Q, La Cava A, Campagnolo DI, Van Kaer L and Shi FD: Expansion of regulatory T cells via IL-2/anti-IL-2 mAb complexes suppresses experimental myasthenia. Eur J Immunol. 40:1577–1589. 2010. View Article : Google Scholar : PubMed/NCBI
11	Meng X, Zhang K, Li J, Dong M, Yang J, An G, Qin W, Gao F, Zhang C and Zhang Y: Statins induce the accumulation of regulatory T cells in atherosclerotic plaque. Mol Med. 18:598–605. 2012. View Article : Google Scholar : PubMed/NCBI
12	Li M, Lin YP, Chen JL, Li H, Jiang RC and Zhang JN: Role of regulatory T cell in clinical outcome of traumatic brain injury. Chin Med J (Engl). 128:1072–1078. 2015. View Article : Google Scholar : PubMed/NCBI
13	Sakaguchi S, Sakaguchi N, Asano M, Itoh M and Toda M: Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol. 155:1151–1164. 1995.PubMed/NCBI
14	Sakaguchi S, Miyara M, Costantino CM and Hafler DA: FOXP3⁺ regulatory T cells in the human immune system. Nat Rev Immunol. 10:490–500. 2010. View Article : Google Scholar : PubMed/NCBI
15	Vignali DA, Collison LW and Workman CJ: How regulatory T cells work. Nat Rev Immunol. 8:523–532. 2008. View Article : Google Scholar : PubMed/NCBI
16	Yuan R, Maeda Y, Li W, Lu W, Cook S and Dowling P: Erythropoietin: A potent inducer of peripheral immuno/inflammatory modulation in autoimmune EAE. PLoS One. 3:e19242008. View Article : Google Scholar : PubMed/NCBI
17	Dénes A, Humphreys N, Lane TE, Grencis R and Rothwell N: Chronic systemic infection exacerbates ischemic brain damage via a CCL5 (regulated on activation, normal T-cell expressed and secreted)-mediated proinflammatory response in mice. J Neurosci. 30:10086–10095. 2010. View Article : Google Scholar : PubMed/NCBI
18	Bassil R, Zhu B, Lahoud Y, Riella LV, Yagita H, Elyaman W and Khoury SJ: Notch ligand delta-like 4 blockade alleviates experimental autoimmune encephalomyelitis by promoting regulatory T cell development. J Immunol. 187:2322–2328. 2011. View Article : Google Scholar : PubMed/NCBI
19	Louveau A, Smirnov I, Keyes TJ, Eccles JD, Rouhani SJ, Peske JD, Derecki NC, Castle D, Mandell JW, Lee KS, et al: Structural and functional features of central nervous system lymphatic vessels. Nature. 523:337–341. 2015. View Article : Google Scholar : PubMed/NCBI
20	Sakaguchi S, Ono M, Setoguchi R, Yagi H, Hori S, Fehervari Z, Shimizu J, Takahashi T and Nomura T: Foxp3⁺ CD25⁺ CD4⁺ natural regulatory T cells in dominant self-tolerance and autoimmune disease. Immunol Rev. 212:8–27. 2006. View Article : Google Scholar : PubMed/NCBI
21	Ghajar J: Traumatic brain injury. Lancet. 356:923–929. 2000. View Article : Google Scholar : PubMed/NCBI
22	Ziebell JM and Morganti-Kossmann MC: Involvement of pro- and anti-inflammatory cytokines and chemokines in the pathophysiology of traumatic brain injury. Neurotherapeutics. 7:22–30. 2010. View Article : Google Scholar : PubMed/NCBI
23	Scheffold A, Murphy KM and Hofer T: Competition for cytokines: T(reg) cells take all. Nat Immunol. 8:1285–1287. 2007. View Article : Google Scholar : PubMed/NCBI
24	Zhang Q, Cui F, Fang L, Hong J, Zheng B and Zhang JZ: TNF-alpha impairs differentiation and function of TGF-beta-induced Treg cells in autoimmune diseases through Akt and Smad3 signaling pathway. J Mol Cell Biol. 5:85–98. 2013. View Article : Google Scholar : PubMed/NCBI
25	Nagamoto-Combs K, McNeal DW, Morecraft RJ and Combs CK: Prolonged microgliosis in the rhesus monkey central nervous system after traumatic brain injury. J Neurotrauma. 24:1719–1742. 2007. View Article : Google Scholar : PubMed/NCBI
26	Abbott NJ: Inflammatory mediators and modulation of blood-brain barrier permeability. Cell Mol Neurobiol. 20:131–147. 2000. View Article : Google Scholar : PubMed/NCBI
27	Amiry-Moghaddam M and Ottersen OP: The molecular basis of water transport in the brain. Nat Rev Neurosci. 4:991–1001. 2003. View Article : Google Scholar : PubMed/NCBI
28	Balda MS, Whitney JA, Flores C, González S, Cereijido M and Matter K: Functional dissociation of paracellular permeability and transepithelial electrical resistance and disruption of the apical-basolateral intramembrane diffusion barrier by expression of a mutant tight junction membrane protein. J Cell Biol. 134:1031–1049. 1996. View Article : Google Scholar : PubMed/NCBI
29	Di Giovanni S, Movsesyan V, Ahmed F, Cernak I, Schinelli S, Stoica B and Faden AI: Cell cycle inhibition provides neuroprotection and reduces glial proliferation and scar formation after traumatic brain injury. Proc Natl Acad Sci USA. 102:8333–8338. 2005. View Article : Google Scholar : PubMed/NCBI
30	Ramlackhansingh AF, Brooks DJ, Greenwood RJ, Bose SK, Turkheimer FE, Kinnunen KM, Gentleman S, Heckemann RA, Gunanayagam K, Gelosa G, et al: Inflammation after trauma: Microglial activation and traumatic brain injury. Ann Neurol. 70:374–383. 2011. View Article : Google Scholar : PubMed/NCBI
31	Sakaguchi S: Naturally arising Foxp3-expressing CD25⁺CD4⁺ regulatory T cells in immunological tolerance to self and non-self. Nat Immunol. 6:345–352. 2005. View Article : Google Scholar : PubMed/NCBI
32	Schwartz RH: Natural regulatory T cells and self-tolerance. Nat Immunol. 6:327–330. 2005. View Article : Google Scholar : PubMed/NCBI
33	La Cava A, Van Kaer L and Fu-Dong-Shi: CD4⁺CD25⁺ Tregs and NKT cells: Regulators regulating regulators. Trends Immunol. 27:322–327. 2006. View Article : Google Scholar : PubMed/NCBI
34	Balandina A, Lécart S, Dartevelle P, Saoudi A and Berrih-Aknin S: Functional defect of regulatory CD4(+)CD25(+) T cells in the thymus of patients with autoimmune myasthenia gravis. Blood. 105:735–741. 2005. View Article : Google Scholar : PubMed/NCBI
35	Fattorossi A, Battaglia A, Buzzonetti A, Ciaraffa F, Scambia G and Evoli A: Circulating and thymic CD4 CD25 T regulatory cells in myasthenia gravis: Effect of immunosuppressive treatment. Immunology. 116:134–141. 2005. View Article : Google Scholar : PubMed/NCBI
36	Liu R, La Cava A, Bai XF, Jee Y, Price M, Campagnolo DI, Christadoss P, Vollmer TL, Van Kaer L and Shi FD: Cooperation of invariant NKT cells and CD4⁺CD25⁺ T regulatory cells in the prevention of autoimmune myasthenia. J Immunol. 175:7898–7904. 2005. View Article : Google Scholar : PubMed/NCBI
37	Ji J and Cloyd MW: HIV-1 binding to CD4 on CD4+CD25+ regulatory T cells enhances their suppressive function and induces them to home to, and accumulate in, peripheral and mucosal lymphoid tissues: An additional mechanism of immunosuppression. Int Immunol. 21:283–294. 2009. View Article : Google Scholar : PubMed/NCBI