巨噬細(xì)胞在骨骼肌損傷修復(fù)過程中的作用①

崔琳 沈亞南 楊月琴

(1.武漢體育學(xué)院研究生院;2.武漢大學(xué)中南醫(yī)院;3.武漢體育學(xué)院 湖北武漢 430079)

巨噬細(xì)胞在骨骼肌損傷修復(fù)過程中的作用①

崔琳1沈亞南2楊月琴3

(1.武漢體育學(xué)院研究生院;2.武漢大學(xué)中南醫(yī)院;3.武漢體育學(xué)院 湖北武漢 430079)

骨骼肌急性損傷在日常生活中十分常見,尤其多發(fā)生于現(xiàn)今長期靜坐少動人群和活潑好動的青少年中。巨噬細(xì)胞的兩個亞型均被證實(shí)在人體骨骼肌損傷和再生過程中起著至關(guān)重要的作用。在骨骼肌損傷后的不同階段,巨噬細(xì)胞表現(xiàn)出不同的亞型,其功能和作用效果也不同。M1巨噬細(xì)胞具有較高的促炎性,能夠清除損傷病灶,促進(jìn)成肌細(xì)胞的增殖而抑制其分化;M2巨噬細(xì)胞通過分泌多種不同的細(xì)胞因子來抑制炎癥反應(yīng)的進(jìn)一步發(fā)生,并促進(jìn)和改善纖維重建。該文將對骨骼肌損傷修復(fù)過程中,不同亞型巨噬細(xì)胞所表現(xiàn)出的不同作用進(jìn)行針對性的闡述,為骨骼肌損傷后的愈合修復(fù)研究提供參考。

骨骼肌損傷 巨噬細(xì)胞M1 巨噬細(xì)胞M2 骨骼肌修復(fù)

骨骼肌急性損傷是發(fā)生在日常生活中的常見現(xiàn)象,尤其多發(fā)生于現(xiàn)今長期靜坐少動人群和活潑好動的青少年中,因損傷導(dǎo)致的疼痛、腫脹,甚至粘連,嚴(yán)重影響人們的活動能力,其恢復(fù)過程必須引起高度重視。目前已有大量研究表明,骨骼肌損傷主要由以下幾個方面引起:(1)直接挫傷;(2)自由基損傷;(3)鈣離子超載;(4)炎性反應(yīng)。骨骼肌損傷愈合經(jīng)歷了有序而又重合的復(fù)雜病理生理過程,包括組織降解、炎癥反應(yīng)、骨骼肌再生以及纖維瘢痕組織形成[1]。巨噬細(xì)胞作為人體天然免疫的第一道屏障,其促炎和抗炎活動是骨骼肌損傷愈合和骨骼肌再生的生理基礎(chǔ)[2]。

1 骨骼肌組織損傷后愈合過程中的骨骼肌再生現(xiàn)象

骨骼肌損傷修復(fù)主要是成肌細(xì)胞(肌衛(wèi)星細(xì)胞)的激活、增殖、遷移、分化及融合的過程[3]。骨骼肌內(nèi)衛(wèi)星細(xì)胞,位于基底膜下,在外界相應(yīng)的刺激下,衛(wèi)星細(xì)胞一方面繼續(xù)在局部增殖,形成衛(wèi)星細(xì)胞池,另一方面能夠遷移損傷部位,分化融合形成成熟的骨骼肌細(xì)胞[4]。衛(wèi)星細(xì)胞特異性膜糖蛋白為NCAM(CD56和Leu19),核蛋白為轉(zhuǎn)錄因子Pax7[5]。Myomaker在肌原纖維融合過程中表達(dá)在成肌細(xì)胞的細(xì)胞表面,融合完成后其表達(dá)會下調(diào)[6]。肌生成抑制蛋白(mypsstatin, MSTN)和卵泡抑素(follistatin,FSTN)常用來評價骨骼肌損傷后的不同階段,MSTN是轉(zhuǎn)化生長因子-β(transforming growth factor-β,TGF-β)超家族成員,骨骼肌、心臟及脂肪組織中均有表達(dá),在骨骼肌損傷修復(fù)的降解階段,損傷的肌纖維和結(jié)締組織中,有MSTN的表達(dá),MSTN可能通過抑制衛(wèi)星細(xì)胞的增殖,從而抑制損傷后骨骼肌的再生;而FSTN能夠有效的抑制MSTN的作用,刺激衛(wèi)星細(xì)胞的增殖和骨骼肌再生[7]。ADAM12和結(jié)蛋白(desmin)在骨骼肌損傷后的表達(dá)情況也存在一定的差別,ADAM12主要在衛(wèi)星細(xì)胞增殖過程中表達(dá),而Desmin通常在骨骼肌細(xì)胞分化成熟過程中表達(dá),因此,兩者分別提示骨骼肌損傷愈合的不同階段。衛(wèi)星細(xì)胞在上述相關(guān)調(diào)節(jié)因素作用下,在骨骼肌損傷修復(fù)過程中增殖、分化成成熟骨骼肌細(xì)胞,不同階段的功能狀態(tài),也是制約著骨骼肌損傷的修復(fù)的因素,必須對衛(wèi)星細(xì)胞增殖、分化成熟進(jìn)行分階段性研究。骨骼肌發(fā)生損傷后,成纖維細(xì)胞分泌大量趨化因子,如基質(zhì)細(xì)胞來源因子(stromal cell-derived factor 1,SDF-1)、成纖維細(xì)胞生長因子(fibroblast growth factor, FGF)以及肝細(xì)胞生長因子(hepatoccyte growth factor, HGF)等,前者能夠趨化骨骼肌前體細(xì)胞至損傷部位,后兩者是骨骼肌再生過程中的重要調(diào)節(jié)因子。巨噬細(xì)胞和中性粒細(xì)胞也分泌著多種細(xì)胞因子[8],影響成肌細(xì)胞的增殖、分化、融合。

2 巨噬細(xì)胞在骨骼肌損傷恢復(fù)過程中的作用

骨骼肌急性損傷后,將分泌FGF、血小板衍生因子(platelet derived growth factor, PDGF)等[9],強(qiáng)烈趨化中性粒細(xì)胞、單核細(xì)胞、巨噬細(xì)胞等免疫細(xì)胞至損傷部位,中性粒細(xì)胞在骨骼肌損傷后2小時達(dá)到高峰;巨噬細(xì)胞在6-24小時達(dá)到高峰;傷后3d,中性粒細(xì)胞和巨噬細(xì)胞數(shù)量迅速降低。另外,成肌細(xì)胞也分泌相關(guān)細(xì)胞因子[10]如:單核細(xì)胞趨化蛋白(monocyte chemoattractant protein,MCP1/CCL2)、趨化因子(fractalkine,CX3CL1)、巨噬細(xì)胞來源的趨化因子(macrophage derived chemokine,MDC)、血管內(nèi)皮生長因子(vascular endothelial growth factor,VEGF)、尿激酶(urokinase)系統(tǒng)等趨化巨噬細(xì)胞至受傷部位。在各種趨化因子作用下,骨髓來源表達(dá)MCP1/CCL2受體(CCR2)的單核細(xì)胞,迅速趨化至骨骼肌損傷部位,積極參與骨骼肌修復(fù)過程,CCR2的缺失,嚴(yán)重影響了骨骼肌的修復(fù)[11]。大量研究證實(shí),骨骼肌急性損傷時,位于肌外膜/肌束膜附近經(jīng)典巨噬細(xì)胞受到趨化繼中性粒細(xì)胞之后首先到達(dá)損傷部位,隨后,在各種化學(xué)趨化作用下,外周血液中巨噬細(xì)胞到達(dá)損傷部位,急性損傷1d后,巨噬細(xì)胞數(shù)量達(dá)到最大。

巨噬細(xì)胞對于肌纖維的再生是必不可少的,但也導(dǎo)致其纖維化。巨噬細(xì)胞在組織修復(fù)過程中的這種功能上的鮮明對比性,是由于巨噬細(xì)胞在不同刺激下表現(xiàn)出不同表型和功能。當(dāng)前研究的數(shù)據(jù)表明,在創(chuàng)傷性肌肉損傷后,肌肉纖維化的愈合過程中增加了巨噬細(xì)胞的堆積。然而,巨噬細(xì)胞在骨骼肌損傷即刻既沒有表現(xiàn)出M1型,也未出現(xiàn)M2型。反而,巨噬細(xì)胞在骨骼肌損傷后的早期表達(dá)出了M1和M2的混合標(biāo)記物,隨后這些標(biāo)記物的表達(dá)量增加,尤其是IL-10 mRNA 和蛋白質(zhì)分泌物,在肌纖維損傷3天后的巨噬細(xì)胞中大幅升高。此外,盡管促炎和抗炎兩個過程中巨噬細(xì)胞亞型的不同可被認(rèn)定為是基于TNF α的不同水平來決定的,但這并沒有明確就是M1和M2型。重要的是,M1巨噬細(xì)胞可減少膠原蛋白積累并且增加損傷肌纖維的再生。在體組織外傷的修復(fù)過程中,這些發(fā)現(xiàn)改善了大家對巨噬細(xì)胞表型的認(rèn)識,并且為潛在的基于巨噬細(xì)胞的治療方法來促進(jìn)損傷肌纖維修復(fù)提出了獨(dú)到見解[12]。

巨噬細(xì)胞的兩個亞型均被證實(shí)存在于損傷和再生階段的人體肌纖維中。在應(yīng)對外界環(huán)境的變化時它們會出動促炎因子M1或者抗炎因子M2這兩個表型中的一個。巨噬細(xì)胞表達(dá)M1標(biāo)記物時優(yōu)先與增殖的肌衛(wèi)星細(xì)胞結(jié)合,然而在成肌分化時主要表達(dá)抗炎的M2巨噬細(xì)胞標(biāo)記物。由此可見,損傷后的不同階段,巨噬細(xì)胞類型不同,表現(xiàn)出的作用、效果也不同,巨噬細(xì)胞能夠清除損傷病灶,促進(jìn)生肌前體細(xì)胞增殖、分化,抑制骨骼肌細(xì)胞的凋亡,促進(jìn)血管再生。在急性損傷后,M1型巨噬細(xì)胞首先滲入到損傷部位來對壞死的細(xì)胞碎片進(jìn)行清理,隨之,M2型巨噬細(xì)胞則在其之后出現(xiàn)以促進(jìn)組織的愈合。有研究人員為了證明巨噬細(xì)胞是由早期的M1型轉(zhuǎn)變?yōu)镸2型的,分別從損傷和未損傷的肌纖維中通過磁性分離選出巨噬細(xì)胞,來檢查M1和M2型巨噬細(xì)胞相關(guān)基因的表達(dá)。與未損傷肌纖維中分離的固有巨噬細(xì)胞相比,損傷組在損傷后1～3天,肌纖維巨噬細(xì)胞中M1相關(guān)細(xì)胞因子IL-1β和TNFα的表達(dá)有所升高,隨后降低至未損傷組水平。

所有影響巨噬細(xì)胞上述功能的因素,均會影響骨骼肌損傷修復(fù)效果,因此,有必要根據(jù)巨噬細(xì)胞功能狀態(tài)的不同,進(jìn)行針對性的研究。cAMP反應(yīng)元件結(jié)合蛋白(cAMP response element-binding protein,CREB)[13]、MAP激酶磷酸酶-1(MAP kinase phosphatase,MKP-1)[14]、磷酸腺苷蛋白激酶-α1(AMP-activated protein kinase α1,AMPK-α1)[15]、調(diào)節(jié)性T細(xì)胞以及被吞噬的組織碎片均在M1型巨噬細(xì)胞轉(zhuǎn)化為M2型巨噬細(xì)胞過程中,發(fā)揮了重要作用,缺失上述任何因素,將會影響損傷骨骼肌的修復(fù)效果[16]。

3 M1巨噬細(xì)胞對骨骼肌損傷愈合的影響

巨噬細(xì)胞是人體對抗外來病原體的第一道防線,也是組織修復(fù)的主要功能細(xì)胞[17]。經(jīng)典M1型巨噬細(xì)胞能夠被TNF-α、脂多糖(LPS)、GM-CSF,尤其是TNF-α和IFN-γ激活,識別并清除壞死組織、細(xì)胞碎片以及病原體等,表現(xiàn)出高促炎性。M1型巨噬細(xì)胞在骨骼肌急性損傷后1d聚集達(dá)到高峰,不斷吞噬組織碎片,清除損傷組織,分泌大量細(xì)胞因子,如:TNF-α、IL-6、IL-1β和白細(xì)胞蛋白酶抑制劑(secretory leukocyte protease inhibitor,SLPI)促進(jìn)炎性反應(yīng);誘導(dǎo)并活化Th1細(xì)胞,發(fā)動機(jī)體免疫反應(yīng)。這些細(xì)胞因子在肌營養(yǎng)不良型 (mdx)小鼠肌肉中高表達(dá),并且,從病理學(xué)上它們可能促進(jìn)了急性期的肌肉損傷[18]。經(jīng)典M1型巨噬細(xì)胞能夠持續(xù)存在于營養(yǎng)不良的肌肉組織中,是由于持續(xù)的炎癥反應(yīng)和來自iNOS的一氧化氮(NO)所產(chǎn)生的細(xì)胞毒素的水平所誘導(dǎo)的進(jìn)一步的肌纖維損傷[19]。在肌營養(yǎng)不良大鼠中,早期M1浸潤之后,緊接著的是M2巨噬細(xì)胞亞型的募集,CD206,IL-10以及精氨酸酶的表達(dá),它們被稱為M2a;這些細(xì)胞通過對底物精氨酸酶的奪取,來降低NO介導(dǎo)的M1巨噬細(xì)胞的細(xì)胞毒性。M1型巨噬細(xì)胞分泌的TNF-α能夠促進(jìn)成肌細(xì)胞的增殖而抑制其分化;IL-6能夠刺激骨骼肌衛(wèi)星細(xì)胞的增殖及骨骼肌的生長;IL-4能夠促進(jìn)肌原細(xì)胞融合;在幼型的mdx鼠中,抗體和TNF-α藥物阻斷會使得損傷骨骼肌數(shù)量和骨骼肌持續(xù)損傷現(xiàn)象的顯著減少[20-21]。離體試驗(yàn)中,從mdx型肌纖維分離的有IFN-γ刺激的巨噬細(xì)胞顯著增加了肌細(xì)胞的溶解。然而,幼型mdx鼠在體試驗(yàn)中,IFN-γ的消除并沒有對肌纖維損傷產(chǎn)生影響,并且只是一部分地減少了iNOS的表達(dá),沒有減少巨噬細(xì)胞的細(xì)胞毒性[22]。

4 M2巨噬細(xì)胞對骨骼肌損傷愈合的影響

隨著M1型巨噬細(xì)胞對損傷組織的清除[23]和組織微環(huán)境的變化,巨噬細(xì)胞功能發(fā)生轉(zhuǎn)換,即急性損傷3d后,逐漸轉(zhuǎn)化為抗炎性的M2型巨噬細(xì)胞[24-25]。M2型巨噬細(xì)胞在M-CSF以及IL-4或IL-13存在的情況下被激活,參與活化Th2細(xì)胞,清除寄生蟲,抑制炎癥反應(yīng),促進(jìn)血管增生和組織重塑。

M2巨噬細(xì)胞通過分泌大量的IL-10、IL-10、IGF-1等細(xì)胞因子來抑制炎癥反應(yīng)的進(jìn)一步發(fā)生[26-27]。此外,他們通過分泌多種細(xì)胞因子來促進(jìn)和維持纖維重建,促進(jìn)骨骼肌細(xì)胞的分化形成和抑制其凋亡。例如IGF-1和IL-10,TGF-β等細(xì)胞因子。IGF-1能夠通過磷酸化Akt,使叉頭轉(zhuǎn)錄因子O(forkhead box O,FOXO)失活,從而抑制蛋白的降解,達(dá)到抑制骨骼肌細(xì)胞凋亡的作用[28];IL-10主要源自于浸潤巨噬細(xì)胞,其分泌物是維持肌原細(xì)胞活性和生肌前體細(xì)胞最終分化、融合形成骨骼肌細(xì)胞的關(guān)鍵因子[29];TGF-β通過TLR4受體調(diào)節(jié)傷口的愈合;VEGF-α能夠促進(jìn)損傷骨骼肌部位的血管再生[30]。M1型巨噬細(xì)胞轉(zhuǎn)化為M2型巨噬細(xì)胞不僅為骨骼肌再生和修復(fù)提供了微環(huán)境,還抑制了炎癥的進(jìn)一步發(fā)生,降低免疫反應(yīng)對損傷部位的二次損傷[31]。

5 展望

過去幾年的研究中,逐漸強(qiáng)調(diào)了巨噬細(xì)胞在組織修復(fù)和重建方面的重要作用。骨骼肌急性損傷后,促炎巨噬細(xì)胞M1首先到達(dá)損傷區(qū)域,不斷吞噬組織碎片,清除損傷組織,分泌大量細(xì)胞因子,促進(jìn)炎癥反應(yīng)發(fā)生;隨后由于組織微環(huán)境的變化,M2巨噬細(xì)胞通過分泌不同的細(xì)胞因子來抑制炎癥反應(yīng)的進(jìn)一步發(fā)生,并且維持組織的修復(fù)和再生。但是關(guān)于M1型和M2型巨噬細(xì)胞在骨骼肌損傷愈合過程中的具體調(diào)控機(jī)制仍待進(jìn)一步研究。從而為進(jìn)一步揭示巨噬細(xì)胞在骨骼肌損傷愈合過程中的調(diào)控機(jī)制,為探索出以通過調(diào)控巨噬細(xì)胞來促進(jìn)骨骼肌損傷愈合為重要靶點(diǎn)的治療方法提供有效參考。

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The Function of Macrophages in Skeletal Muscle Injury Repair Process

Cui Lin1Shen Ya’nan2Yang Yueqin3
(1.Graduate School of Wuhan Sports University;2.Zhong Nan Hospital of Wuhan University;3.Wuhan Sports University,Wu HanHubei Province,430079,China)

The acute skeletal muscle injury is very common in our daily life,especially develops during the lively teenagers and people who are always sitting still.It is confirmed that the two different hypotypes are playing a vital role in the human myofibers injury and regeneration. The macrophage put up different hypotypes which could present different effects,during the different stages after muscle injury.Macrophages expressing M1 markers infiltrate early to promote the clearance of necrotic debris,also promote the proliferation and inhibit the differentiation of myoblast.Whereas M2 macrophages appears to inhibit inflammation reaction and sustain tissue healing.All the factors above could influence the effect of skeletal muscle injury repair.So that,we pointedly expound the different function of macrophages under different condition.

Skeletal muscle injury;MacrophageM1;MacrophageM2; Skeletal muscle repair

G804

A

2095-2813(2015)11(c)-0016-04

10.16655/j.cnki.2095-2813.2015.33.016

運(yùn)動誘導(dǎo)的短跑健將(同卵雙生)基因表達(dá)差異研究(2014JK02)。