中脑星形胶质细胞源性神经营养因子在视网膜Müller细胞中诱导激活p44/42丝裂原活化蛋白激酶信号通路的实验研究

doi:10.3877/cma.j.issn.2095-2007.2019.06.002

中华眼科医学杂志(电子版) ›› 2019, Vol. 09 ›› Issue (06) : 328 -334. doi: 10.3877/cma.j.issn.2095-2007.2019.06.002

论著

中脑星形胶质细胞源性神经营养因子在视网膜Müller细胞中诱导激活p44/42丝裂原活化蛋白激酶信号通路的实验研究

裴雪婷¹^,^†(

), 卢建民², Yiwen Li³, Rong Wen³

^1. 100730　首都医科大学附属北京同仁医院　北京同仁眼科中心　北京市眼科学与视觉科学重点实验室
^2. 116011　大连医科大学第一附属医院眼科
^3. 33136　美国迈阿密大学巴斯康·帕默眼科研究所

收稿日期:2019-10-16 出版日期:2019-12-28
通信作者: 裴雪婷
基金资助:
国家自然科学基金项目(81300737); 美国国立卫生研究院资助项目(R01EY015289，R01EY018586); 美国佛罗里达州视觉希望计划(08KN-09，2KF02)

MANF induced p44/42MAPK phosphorylation in retinal Müller cells

Xueting Pei¹^,^†(), Jianmin Lu², Yiwen Li³, Rong Wen³

^1. Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Ophthalmology & Visual Science Key Laboratory, Beijing 100730, China
^2. Department of Ophthalmology, First Affiliated Hospital, Dalian Medical University, Dalian 116011, China
^3. Bascom Palmer Eye Institute University of Miami, Miami, FL 33136, USA

Received:2019-10-16 Published:2019-12-28
Corresponding author: Xueting Pei

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引用本文：

裴雪婷, 卢建民, Yiwen Li, Rong Wen. 中脑星形胶质细胞源性神经营养因子在视网膜Müller细胞中诱导激活p44/42丝裂原活化蛋白激酶信号通路的实验研究[J]. 中华眼科医学杂志(电子版), 2019, 09(06): 328-334.

Xueting Pei, Jianmin Lu, Yiwen Li, Rong Wen. MANF induced p44/42MAPK phosphorylation in retinal Müller cells[J]. Chinese Journal of Ophthalmologic Medicine(Electronic Edition), 2019, 09(06): 328-334.

目的

中脑星形胶质细胞源性神经营养因子(MANF)可能对视网膜光感受器细胞和视网膜神经节细胞具有保护性作用。但是其作用机制还不清楚。本研究探索MANF在视网膜上的作用通路，为其在眼科的应用奠定基础。

方法

选用Sprague-Dawley雄性大鼠25只，体重0.2~0.25 kg。采用数字表法，随机将大鼠分为未处理组和处理组。其中，未处理组5只，处理组左眼注射重组人MANF10 μg (3 μl)，右眼注射磷酸盐缓冲液(PBS)3 μl，分别于注射后0.5 h、1 h、2 h及4 h四个时间点取材视网膜，每个时间点5只大鼠。新生大鼠视网膜分离培养原代Müller细胞，100ng/ml MANF处理细胞后，在不同时间点收集细胞Western blot检测磷酸化p44/42丝裂原活化蛋白激酶(MAPK)的表达水平，冰冻切片免疫组化检测MANF诱导活化的磷酸化p44/42MAPK在视网膜上的定位。以Image J图像分析软件分析图像，Western blot条带密度比值和免疫荧光强度为计量资料以(±s)表示；各时间点与未处理组组间，采用独立样本t检验的方法进行比较。

结果

SD大鼠玻璃体腔注射MANF后，磷酸化p44/42MAPK的表达在0.5 h就开始明显升高，1 h达到高峰，较对照玻璃体腔注射PBS组和未处理组差异均具有统计学意义(t＝21.18，4.41；P<0.05)，然后逐渐下降，4 h降至未处理组水平。冰冻切片免疫组化检查结果显示磷酸化p44/42MAPK阳性的细胞位于视网膜内核层的Müller细胞，其荧光强度显著高于阴性未处理组，差异有统计学意义(t＝11.41，P<0.05)。原代培养的Müller细胞经MANF处理后，磷酸化p44/42MAPK在5 min时较未处理组就有显著升高，差异有统计学意义(t＝4.48，6.43；P<0.05)，15 min达到高峰，差异有统计学意义(t＝19.57，9.18；P<0.05)，到30 min降至正常水平。

结论

p44/42MAPK信号通路参与了MANF的神经保护作用机制。MANF直接作用于视网膜Müller细胞，可能通过与Müller细胞的相互作用起到细胞保护性作用。

关键词: 中脑星形胶质细胞源性神经营养因子, p44/42丝裂原活化蛋白激酶信号通路, 视网膜, Müller细胞

Objective

Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a potent neurotrophic factor for photoreceptors and retinal ganglion cells. But the mechanism underlying its neuroprotective effects is not well understood. Our present work investigate potential signaling mechanism and pathway underlying these action effects.

Methods

25 Sprague-Dawley male rats (weight 0.2 to 0.25 kg) were selected. They were randomly divided into untreated group and 4 treated groups with different treating time. There were 5 rats in each group. In treated group, the left eyes of SD rats were injected intravitreally with 10 μg MANF (3 μl), and the right eyes were injected with 3 μl PBS (phosphate buffered saline) as negative controls. Retinas were collected at 0.5 h, 1 h, 2 h, 4 h after injection. Müller cells were isolated from rat retina and cultured in DMEM + 10% fetal bovine serum. Cells were treated with MANF (100 ng/ml) and collected at given time points after addition of MANF. The levels of phospho-p44/42MAPK wereassessed by Western blot analysis. Immunohistochemical analysis using frozen section was employed to localize the MANF-induced phospho-p44/42MAPK. Images were analyzed using Image J analysis system. Relative density ratio of Western blot bands and immune fluorescence intensity were represented as means±standard errors(±s). Independent sample t test was used to compare MANF treated and control groups.

Results

A dramatic significant increase in phospho-p44/42MAPK was detected 30 min after MANF injection into the vitreous, and increase to the peak at 1 hour (t=21.18, 4.41; P<0.05), then declined to normal level at 4 hours. Immunostaining for phospho-p44/42MAPK detected a group of positive cells in the inner nuclear layer, with characteristics of Müller cells. The immune fluorescence intensity was significantly stronger than control group (t=11.41, P<0.05). The MANF-induced phospho-p44/42MAPK was confirmed in cultured Müller cells. Addition of MANF (100 ng/ml) to culture medium induced a significant increase in phospho-p44/42MAPK as soon as 5 min (t=4.48, 6.43; P<0.05). The increase in phospho-p44/42MAPK reached a peak at 15 min after treatment (t=19.57, 9.18; P<0.05) and declined to normal level by 30 min.

Conclusions

This data strongly suggests that the p44/42MAPK pathway is involved in mediating extracellular neurotrophic activity of MANF. Experiments with cultured Müller cells could provide the evidence that MANF directly had the interaction with Müller cells.

Key words: MANF, p44/42MAPK pathway, Retina, Müllercells

图3 共聚焦显微镜下玻璃体腔注射1 h后磷酸化p44/42丝裂原活化蛋白激酶冰冻切片免疫荧光显微结构图　图3A、3B及3C示注射磷酸盐缓冲液1 h后的冰冻切片免疫荧光染色图；图3D、3E示注射中脑星形胶质细胞源性神经营养因子1 h后的冰冻切片免疫荧光染色图；图3A、3D示蓝色荧光为4', 6-二脒基-2-苯基吲哚染色标记细胞核的位置；图3B、3E示红色荧光为Cy3荧光标记的羊抗兔二抗，一抗为兔抗人磷酸化p44/42丝裂原活化蛋白激酶抗体；图3C、3F示融合后的图像。中脑星形胶质细胞源性神经营养因子处理组较未处理组的磷酸化p44/42丝裂原活化蛋白激酶表达显著增强，细胞形态定位于视网膜Müller细胞(×20)

表1 SD大鼠未处理组与处理组各时间段Western blot条带磷酸化p44/42MAPK与p44/42MAPK密度比值的比较(±s)

分组		鼠数	磷酸盐缓冲液处理		中脑星形胶质细胞源性神经营养因子处理
分组		鼠数	磷酸化p44MAPK/p44MAPK	磷酸化p42MAPK/p42MAPK	磷酸化p44MAPK/p44MAPK	磷酸化p42MAPK/p42MAPK
未处理组		5	0.61±0.039	0.54±0.090	0.61±0.039	0.54±0.090
处理组
	0.5 h组	5	0.55±0.064	0.43±0.038	1.32±0.130^*	0.95±0.026*
	1 h组	5	0.88±0.032	0.89±0.058	2.61±0.087^*	1.24±0.075^*
	2 h组	5	0.49±0.104	0.53±0.075	0.37±0.069	0.62±0.054
	4 h组	5	0.42±0.057	0.43±0.026	0.35±0.041	0.38±0.022

表1 SD大鼠未处理组与处理组各时间段Western blot条带磷酸化p44/42MAPK与p44/42MAPK密度比值的比较(±s)

分组		鼠数	磷酸盐缓冲液处理		中脑星形胶质细胞源性神经营养因子处理
分组		鼠数	磷酸化p44MAPK/p44MAPK	磷酸化p42MAPK/p42MAPK	磷酸化p44MAPK/p44MAPK	磷酸化p42MAPK/p42MAPK
未处理组		5	0.61±0.039	0.54±0.090	0.61±0.039	0.54±0.090
处理组
	0.5 h组	5	0.55±0.064	0.43±0.038	1.32±0.130^*	0.95±0.026*
	1 h组	5	0.88±0.032	0.89±0.058	2.61±0.087^*	1.24±0.075^*
	2 h组	5	0.49±0.104	0.53±0.075	0.37±0.069	0.62±0.054
	4 h组	5	0.42±0.057	0.43±0.026	0.35±0.041	0.38±0.022

表2 未处理组与处理组大鼠视网膜Müller细胞Western blot条带磷酸化p44/42MAPK与p44/42MAPK密度比值的比较(±s)

分组		鼠数	中脑星形胶质细胞源性神经营养因子处理
分组		鼠数	磷酸化p44MAPK/p44MAPK	磷酸化p42MAPK/p42MAPK
未处理组		5	0.28±0.032	0.37±0.018
处理组
	5 min组	5	0.65±0.092^*	0.81±0.045^*
	15 min组	5	1.46±0.074^*	1.12±0.025^*
	30 min组	5	0.20±0.034	0.24±0.065
	60 min组	5	0.15±0.016	0.18±0.103

表2 未处理组与处理组大鼠视网膜Müller细胞Western blot条带磷酸化p44/42MAPK与p44/42MAPK密度比值的比较(±s)

分组		鼠数	中脑星形胶质细胞源性神经营养因子处理
分组		鼠数	磷酸化p44MAPK/p44MAPK	磷酸化p42MAPK/p42MAPK
未处理组		5	0.28±0.032	0.37±0.018
处理组
	5 min组	5	0.65±0.092^*	0.81±0.045^*
	15 min组	5	1.46±0.074^*	1.12±0.025^*
	30 min组	5	0.20±0.034	0.24±0.065
	60 min组	5	0.15±0.016	0.18±0.103

[1]	Petrova P, Raibekas A, Pevsner J, et al. MANF: a new mesencephalic, astrocyte-derived neurotrophic factor with selectivity for dopaminergic neurons[J]. J Mol Neurosci, 2003, 20(2): 173-188.
[2]	Palgi M, Lindstrom R, Peranen J, et al. Evidence that DmMANF is an invertebrate neurotrophic factor supporting dopaminergic neurons[J]. Proc Natl Acad Sci U S A, 2009, 106(7): 2429-2434.
[3]	Voutilainen MH, Back S, Porsti E, et al. Mesencephalic astrocyte-derived neurotrophic factor is neurorestorative in rat model of Parkinson's disease[J]. J Neurosci, 2009, 29(30): 9651-9659.
[4]	Lu J, Luo L, Huang D, et al. Photoreceptor Protection by Mesencephalic Astrocyte-Derived Neurotrophic Factor (MANF)[J]. eNeuro, 2018, 5(2): 109-118.
[5]	Gao FJ, Zhang SH, Li TT, et al. Expression and Distribution of Mesencephalic Astrocyte-Derived Neurotrophic Factor in the Retina and Optic Nerve[J]. Front Hum Neurosci, 2016, 10(1): 686.
[6]	Brooks DE, Garcia GA, Dreyer EB, et al. Vitreous body glutamate concentration in dogs with glaucoma[J]. Am J Vet Res, 1997, 58(8): 864-867.
[7]	Dreyer EB, Zurakowski D, Schumer RA, et al. Elevated glutamate levels in the vitreous body of humans and monkeys with glaucoma[J]. Arch Ophthalmol, 1996, 114(3): 299-305.
[8]	Chen Y, Palczewska G, Mustafi D, et al. Systems pharmacology identifies drug targets for Stargardt disease-associated retinal degeneration[J]. J Clin Invest, 2013, 123(12): 5119-5134.
[9]	Nishimura T, Ishima T, Iyo M, et al. Potentiation of nerve growth factor-induced neurite outgrowth by fluvoxamine: role of sigma-1 receptors, IP3 receptors and cellular signaling pathways[J]. PLoS One, 2008, 3(7): e2558.
[10]	Wen R, Cheng T, Li Y, et al. Alpha 2-adrenergic agonists induce basic fibroblast growth factor expression in photoreceptors in vivo and ameliorate light damage[J]. J Neurosci, 1996, 16(19): 5986-5992.
[11]	Harun-Or-Rashid M, Hallbook F. Alpha 2-Adrenergic Receptor Agonist Brimonidine Stimulates ERK1/2 and AKT Signaling via Transactivation of EGF Receptors in the Human MIO-M1 Muller Cell Line[J]. Curr Eye Res, 2019, 44(1): 34-45.
[12]	Berson EL, Rosner B, Sandberg MA, et al. Clinical trial of lutein in patients with retinitis pigmentosa receiving vitamin A[J]. Arch Ophthalmol, 2010, 128(4): 403-411.
[13]	Ait-Ali N, Fridlich R, Millet-Puel G, et al. Rod-derived cone viability factor promotes cone survival by stimulating aerobic glycolysis[J]. Cell, 2015, 161(4): 817-832.
[14]	Lee SY, Usui S, Zafar AB, et al. N-Acetylcysteine promotes long-term survival of cones in a model of retinitis pigmentosa[J]. J Cell Physiol, 2011, 226(7): 1843-1849.
[15]	Lambiase A, Aloe L, Centofanti M, et al. Experimental and clinical evidence of neuroprotection by nerve growth factor eye drops: Implications for glaucoma[J]. Proc Natl Acad Sci U S A, 2009, 106(32): 13469-13474.
[16]	Mesentier-Louro LA, Rosso P, Carito V, et al. Nerve Growth Factor Role on Retinal Ganglion Cell Survival and Axon Regrowth: Effects of Ocular Administration in Experimental Model of Optic Nerve Injury[J]. Mol Neurobiol, 2019, 56(2): 1056-1069.
[17]	Chen H, Weber AJ. BDNF enhances retinal ganglion cell survival in cats with optic nerve damage[J]. Invest Ophthalmol Vis Sci, 2001, 42(5): 966-974.
[18]	Domenici L, Origlia N, Falsini B, et al. Rescue of retinal function by BDNF in a mouse model of glaucoma[J]. PLoS One, 2014, 9(12): e115579.
[19]	Blanco RE, Vega-Melendez GS, De La Rosa-Reyes V, et al. Application of CNTF or FGF-2 increases the number of M2-like macrophages after optic nerve injury in adult Rana pipiens[J]. PLoS One, 2019, 14(5): e209733.
[20]	Flachsbarth K, Jankowiak W, Kruszewski K, et al. Pronounced synergistic neuroprotective effect of GDNF and CNTF on axotomized retinal ganglion cells in the adult mouse[J]. Exp Eye Res, 2018, 176(11): 258-265.
[21]	Sieving PA, Caruso RC, Tao W, et al. Ciliary neurotrophic factor (CNTF) for human retinal degeneration: phase I trial of CNTF delivered by encapsulated cell intraocular implants[J]. Proc Natl Acad Sci U S A, 2006, 103(10): 3896-3901.
[22]	Sallo FB, Leung I, Clemons TE, et al. Correlation of structural and functional outcome measures in a phase one trial of ciliary neurotrophic factor in type 2 idiopathic macular telangiectasia.[J]. Retina, 2018, 38 (Suppl 1): S27-S32.
[23]	Chew EY, Clemons TE, Jaffe GJ, et al. Effect of Ciliary Neurotrophic Factor on Retinal Neurodegeneration in Patients with Macular Telangiectasia Type 2: A Randomized Clinical Trial[J]. Ophthalmology, 2019, 126(4): 540-549.
[24]	Li S, Sato K, Gordon WC, et al. Ciliary neurotrophic factor (CNTF) protects retinal cone and rod photoreceptors by suppressing excessive formation of the visual pigments[J]. J Biol Chem, 2018, 293(39): 15256-15268.
[25]	Zaccaro MC, Lee HB, Pattarawarapan M, et al. Selective small molecule peptidomimetic ligands of TrkC and TrkA receptors afford discrete or complete neurotrophic activities[J]. Chem Biol, 2005, 12(9): 1015-1028.
[26]	Lebrun-Julien F, Morquette B, Douillette A, et al. Inhibition of p75(NTR) in glia potentiates TrkA-mediated survival of injured retinal ganglion cells[J]. Mol Cell Neurosci, 2009, 40(4): 410-420.
[27]	Ghasemi M, Alizadeh E, Saei AK, et al. Ciliary neurotrophic factor (CNTF) delivery to retina: an overview of current research advancements[J]. Artif Cells Nanomed Biotechnol, 2018, 46(8): 1694-1707.
[28]	Lindholm P, Peranen J, Andressoo JO, et al. MANF is widely expressed in mammalian tissues and differently regulated after ischemic and epileptic insults in rodent brain[J]. Mol Cell Neurosci, 2008, 39(3): 356-371.
[29]	Wang H, Ke Z, Alimov A, et al. Spatiotemporal expression of MANF in the developing rat brain[J]. PLoS One, 2014, 9(2): e90433.
[30]	Hellman M, Arumae U, Yu LY, et al. Mesencephalic astrocyte-derived neurotrophic factor (MANF) has a unique mechanism to rescue apoptotic neurons[J]. J Biol Chem, 2011, 286(4): 2675-2680.
[31]	Cohen H, Lavu S, Bitterman KJ, et al. Acetylation of the C terminus of Ku70 by CBP and PCAF controls Bax-mediated apoptosis[J]. Mol Cell, 2004, 13(5): 627-638.
[32]	Tadimalla A, Belmont PJ, Thuerauf DJ, et al. Mesencephalic Astrocyte-Derived Neurotrophic Factor Is an Ischemia-Inducible Secreted Endoplasmic Reticulum Stress Response Protein in the Heart[J]. Circulation Research, 2008, 103(11): 1249-1258.
[33]	Apostolou A, Shen Y, Liang Y, et al. Armet, a UPR-upregulated protein, inhibits cell proliferation and ER stress-induced cell death[J]. Exp Cell Res, 2008, 314(13): 2454-2467.
[34]	Glembotski CC, Thuerauf DJ, Huang C, et al. Mesencephalic astrocyte-derived neurotrophic factor protects the heart from ischemic damage and is selectively secreted upon sarco/endoplasmic reticulum calcium depletion[J]. J Biol Chem, 2012, 287(31): 25893-25904.
[35]	Cunha DA, Cito M, Grieco FA, et al. Pancreatic beta-cell protection from inflammatory stress by the endoplasmic reticulum proteins thrombospondin 1 and mesencephalic astrocyte-derived neutrotrophic factor (MANF)[J]. J Biol Chem, 2017, 292(36): 14977-14988.
[36]	Hakonen E, Chandra V, Fogarty CL, et al. MANF protects human pancreatic beta cells against stress-induced cell death[J]. Diabetologia, 2018, 61(10): 2202-2214.
[37]	Lindahl M, Danilova T, Palm E, et al. MANF is indispensable for the proliferation and survival of pancreatic beta cells[J]. Cell Rep, 2014, 7(2): 366-375.
[38]	Wang XY, Song MM, Bi SX, et al. MRI Dynamically Evaluates the Therapeutic Effect of Recombinant Human MANF on Ischemia/Reperfusion Injury in Rats[J]. Int J Mol Sci, 2016, 17(9): 1476-1479.
[39]	Airavaara M, Shen H, Kuo CC, et al. Mesencephalic astrocyte-derived neurotrophic factor reduces ischemic brain injury and promotes behavioral recovery in rats[J]. J Comp Neurol, 2009, 515(1): 116-124.
[40]	Airavaara M, Chiocco MJ, Howard DB, et al. Widespread cortical expression of MANF by AAV serotype 7: localization and protection against ischemic brain injury[J]. Exp Neurol, 2010, 225(1): 104-113.
[41]	Miller ML, Alegre ML. Super-MANF to the Rescue: Immunomodulation Improves Retinal Repair and Regenerative Cell Therapy[J]. Am J Transplant, 2017, 17(1): 3.
[42]	Kahn MA, Huang CJ, Caruso A, et al. Ciliary neurotrophic factor activates JAK/Stat signal transduction cascade and induces transcriptional expression of glial fibrillary acidic protein in glial cells[J]. J Neurochem, 1997, 68(4): 1413-1423.
[43]	Sagar SM, Edwards RH, Sharp FR. Epidermal growth factor and transforming growth factor alpha induce c-fos gene expression in retinal Muller cells in vivo[J]. J Neurosci Res, 1991, 29(4): 549-559.
[44]	Ekstrom P, Sanyal S, Narfstrom K, et al. Accumulation of glial fibrillary acidic protein in Muller radial glia during retinal degeneration[J]. Invest Ophthalmol Vis Sci, 1988, 29(9): 1363-1371.

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MANF induced p44/42MAPK phosphorylation in retinal Müller cells

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MANF induced p44/42MAPK phosphorylation in retinal Müller cells