戴鴻宇，季東，談程，孫杰，姚昊

致病性Th17細胞在神經(jīng)炎癥中的作用及調(diào)控機制的研究進展

戴鴻宇1,2，季東1,2，談程1,2，孫杰3，姚昊1,2

1. 南京醫(yī)科大學(xué)第二附屬醫(yī)院心血管中心，南京 210003 2. 南京醫(yī)科大學(xué)第二附屬醫(yī)院麻醉科，南京 210011 3. 東南大學(xué)附屬中大醫(yī)院麻醉科，南京 210009

神經(jīng)炎癥是中樞神經(jīng)系統(tǒng)在損傷、感染、毒素等各種影響內(nèi)穩(wěn)態(tài)因素的刺激下產(chǎn)生的復(fù)雜免疫反應(yīng)，涉及駐留在中樞神經(jīng)系統(tǒng)中的多種免疫細胞。持續(xù)存在的神經(jīng)炎癥是所有神經(jīng)系統(tǒng)疾病(包括神經(jīng)發(fā)育、神經(jīng)退行性和精神性疾病)病因和病程的共同特性。Th17細胞是CD4+T細胞的一個重要亞型，在穩(wěn)態(tài)條件下介導(dǎo)對細胞外細菌和真菌的免疫反應(yīng)，維持腸道粘膜屏障的防御功能。但當(dāng)體內(nèi)細胞因子微環(huán)境發(fā)生炎癥性改變時，Th17細胞可以轉(zhuǎn)化為具有高度促炎性的致病表型，在炎癥性疾病的發(fā)生發(fā)展中起著至關(guān)重要的作用。本文主要對致病性Th17細胞的分化調(diào)控及其在神經(jīng)炎癥中的作用進行了系統(tǒng)綜述，對于理解免疫系統(tǒng)和神經(jīng)系統(tǒng)之間的相互作用具有一定參考意義。

神經(jīng)炎癥；致病性Th17細胞；血腦屏障；RORγt

炎癥是機體對損傷、感染或其他刺激做出的防御性反應(yīng)，一方面，它能夠消除致病因素并修復(fù)組織損傷，另一方面，當(dāng)炎癥反應(yīng)過激或趨于慢性時，會形成炎癥環(huán)境，免疫系統(tǒng)轉(zhuǎn)而攻擊自身組織和細胞，導(dǎo)致進行性損傷。神經(jīng)炎癥是中樞神經(jīng)系統(tǒng)(central nervous system, CNS)在損傷、感染、毒素等各種影響內(nèi)穩(wěn)態(tài)因素的刺激下產(chǎn)生的復(fù)雜免疫反應(yīng)，涉及CNS中的免疫細胞和多種駐留細胞，包括膠質(zhì)細胞(小膠質(zhì)細胞、星形膠質(zhì)細胞、少突膠質(zhì)細胞)、髓樣細胞(巨噬細胞和樹突狀細胞)以及外周白細胞。持續(xù)存在的神經(jīng)炎癥是神經(jīng)系統(tǒng)疾病(如神經(jīng)發(fā)育、神經(jīng)退行性和精神性疾病)病因和病程的共同特性[1]。許多研究表明，神經(jīng)炎癥的嚴(yán)重程度與Th17細胞介導(dǎo)的免疫反應(yīng)之間存在相關(guān)性[2]。Th17細胞作為已證實的致病細胞與多發(fā)性硬化癥(multiple sclerosis, MS)[3]、帕金森病(Parkinson’s disease, PD)[4]等多種神經(jīng)炎癥參與的中樞神經(jīng)系統(tǒng)退行性疾病息息相關(guān)。本文對致病性Th17細胞的分化調(diào)控及其在神經(jīng)炎癥中的作用進行了系統(tǒng)綜述，深入闡述了致病性Th17細胞的產(chǎn)生和致病性的分子調(diào)控機制，對于理解免疫系統(tǒng)和神經(jīng)系統(tǒng)之間的相互作用、預(yù)防中樞神經(jīng)系統(tǒng)疾病并延緩其進展具有一定參考意義。

1 Th17細胞概況

Th17細胞是一類獨立于Th1和Th2的CD4+T細胞亞型，產(chǎn)生標(biāo)志性細胞因子IL-17，特異性表達維甲酸相關(guān)孤兒受體γt (retinoic acid-associated orphan receptor gamma t, RORγt)和信號轉(zhuǎn)導(dǎo)與轉(zhuǎn)錄激活因子3 (signal transducer and activator of trans-cription 3, STAT3)兩種轉(zhuǎn)錄因子，自2005年發(fā)現(xiàn)以來Th17細胞引起了人們的極大關(guān)注[5]。在穩(wěn)態(tài)條件下，Th17細胞介導(dǎo)對細胞外細菌和真菌的免疫反應(yīng)，維持腸道粘膜屏障的防御功能[6]，但當(dāng)體內(nèi)細胞因子微環(huán)境發(fā)生炎癥性改變時，Th17細胞可以轉(zhuǎn)化為具有高度促炎性的致病表型，突破血腦屏障(blood- brain barrier, BBB)并招募更多的免疫細胞參與神經(jīng)炎癥，導(dǎo)致神經(jīng)變性。鑒于Th17細胞在炎癥性疾病和自身免疫性疾病的發(fā)生發(fā)展中具有重要作用，目前已被用于臨床免疫治療的靶標(biāo)。Th17細胞對宿主既有致病性，又有非致病性，而分化為哪一種表型則取決于不同的細胞因子微環(huán)境[7]。鑒于此，越來越多的研究致力于揭示Th17細胞的異質(zhì)性及其調(diào)控機制。

1.1 Th17細胞的異質(zhì)性

Th17細胞的表型和功能特性在體外和體內(nèi)已經(jīng)得到了廣泛的研究。眾多研究結(jié)果表明，Th17細胞具有異質(zhì)性，體現(xiàn)為既有免疫抑制調(diào)節(jié)性又有高度促炎性[8]。根據(jù)過繼轉(zhuǎn)移后是否具有誘導(dǎo)實驗性自身免疫性腦脊髓膜炎(experimental autoimmune encephalomyelitis, EAE)的能力，可將Th17細胞分為致病性Th17細胞(pathogenic Th17 cells, pTh17 cells)和非致病性Th17細胞(non-pathogenic Th17 cells, non-pTh17 cells)兩種表型[9]。

1.2 非致病性Th17細胞的產(chǎn)生與功能

轉(zhuǎn)化生長因子β1 (transforming growth factor beta 1, TGF-β1)和IL-6誘導(dǎo)的Th17細胞多數(shù)情況下被認(rèn)為是non-pTh17細胞(圖1)，甚至在某些腸道疾病中表現(xiàn)出保護作用[10,11]。它表達免疫調(diào)節(jié)細胞因子IL10和IL-4，以及CD5抗原樣蛋白(CD5 molecule- like, CD5L)、IL-9和GATA3 (GATA binding protein 3)等一系列病理生理反應(yīng)的負性調(diào)節(jié)因子[12]。在體內(nèi)穩(wěn)定狀態(tài)下，分枝絲狀桿菌(segmented filamentous bacteria, SFB)誘導(dǎo)生成的non-pTh17細胞駐留在小腸固有層并分泌大量IL-10，具有維持腸道的免疫平衡和組織完整性的功能[6]，這種免疫調(diào)節(jié)和組織駐留功能依賴于c-Maf的調(diào)控[13]。CD5L屬于富含半胱氨酸的清道夫受體超家族，參與脂質(zhì)代謝的調(diào)節(jié)，特別是在維持多不飽和脂肪酸/脂肪酸水平的平衡中發(fā)揮作用。CD5L在non-pTh17細胞中特異性上調(diào)，通過限制其膽固醇衍生配體的獲取來抑制RORγt的轉(zhuǎn)錄活性[9]。

圖1 Th17細胞分化途徑、信號轉(zhuǎn)導(dǎo)因子及細胞因子示意圖

TGF-β1聯(lián)合IL-6有助于Th17細胞的極化，而IL-1β、IL-6、IL-23、TGF-β3的加入使Th17細胞進一步分化為致病性Th17細胞，參與神經(jīng)炎癥性疾病的發(fā)生發(fā)展。根據(jù)參考文獻[9]，使用BioRender.com修改繪制。

1.3 致病性Th17細胞的產(chǎn)生與功能

在抗原呈遞細胞(antigen presenting cells, APCs)分泌的IL-23的刺激下，non-pTh17將轉(zhuǎn)化為具有致病作用的pTh17細胞[14]，這表明IL-23/IL-23R通路在pTh17細胞誘導(dǎo)炎癥反應(yīng)中起著重要作用，缺乏IL-23R (IL-23 receptor)會降低pTh17細胞的致病潛能，并減少其在CNS的聚集。pTh17細胞在CNS中的致病性一方面有賴于其高度表達的粒細胞巨噬細胞集落刺激因子(granulocyte-macrophage colony- stimulating factor, GM-CSF)，這主要由IL-23和RORγt介導(dǎo)[15]，而GM-CSF又可以通過作用于樹突狀細胞(dendritic cells, DCs)提高pTh17細胞IL-23的產(chǎn)量[16]，從而形成一個正反饋回路。另一方面，pTh17細胞兼有Th17和Th1細胞的促炎特性和致病特征，可同時分泌IL-17和IFN-γ (Th1的標(biāo)志性細胞因子)，且共同表達轉(zhuǎn)錄因子RORγt/RORC [小鼠()/人類()]和T-bet (T-box expressed in T cells，Th1細胞的特異性轉(zhuǎn)錄因子)，因此亦被命名為Th17.1細胞[17]。

與non-p17細胞相比，具有強烈Th1傾向性的pTh17細胞具有更強的破壞BBB的能力，使炎癥細胞更易于向CNS浸潤[18]。激活后的pTh17細胞具有更高的增殖效率，并誘導(dǎo)多藥耐藥蛋白1 (multidrug resistance protein 1, MDR1)的表達，而MDR1能潛在地保護pTh17細胞免受治療藥物的影響[19]。此外，pTh17細胞對Tregs (regulatory T cells)的抑制可能有一定的抵抗力[20]?？偟膩碚f，pTh17細胞具有一些典型的炎癥細胞特征，這使它們在CNS中具有高度致病性(圖1)。

2 致病性Th17在神經(jīng)炎癥中的作用機制

pTh17細胞參與神經(jīng)炎癥的發(fā)生發(fā)展已在EAE和MS的相關(guān)研究中證實，而pTh17細胞衍生的細胞因子亦可直接或間接地增強中樞神經(jīng)系統(tǒng)的炎癥反應(yīng)[21]。pTh17細胞誘導(dǎo)并參與神經(jīng)炎癥的相關(guān)機制主要包括如下方面(圖2)。

圖2 致病性Th17細胞參與神經(jīng)炎癥的分子機制示意圖

外周血中的pTh17細胞通過產(chǎn)生促炎細胞因子和細胞黏附分子相互作用突破ECs，削弱BBB的屏障作用，使大量免疫細胞和促炎介質(zhì)涌入CNS，進一步破壞BBB。在CNS中，pTh17細胞的浸潤激活小膠質(zhì)細胞，IL-17/IL-17R信號決定其炎癥因子的表達，并增加ROS的產(chǎn)生，促進中性粒細胞的趨化和聚集?；罨男∧z質(zhì)細胞啟動神經(jīng)元凋亡途徑，最終導(dǎo)致神經(jīng)變性。根據(jù)參考文獻[27,30]，使用BioRender.com修改繪制。

2.1 破壞血腦屏障

BBB是大腦和血液之間的一層內(nèi)皮屏障，能夠選擇性地阻止某些物質(zhì)和免疫細胞進入腦實質(zhì)，并為CNS提供氧氣和關(guān)鍵營養(yǎng)物質(zhì)。高度特化的內(nèi)皮細胞(endothelial cells, ECs)通過與周細胞、血管周圍星形膠質(zhì)細胞和神經(jīng)元相互作用，形成神經(jīng)血管單元(neurovascular unit, NVU)，限制細胞和溶質(zhì)的細胞旁和跨細胞運動，確保了BBB的功能性和完整性[22,23]。穿越BBB是pTh17細胞參與神經(jīng)炎癥的第一步。體外和體內(nèi)研究表明，分泌IFN-γ的pTh17細胞能夠優(yōu)先穿越人類的BBB，且在EAE小鼠和MS患者的腦實質(zhì)病變區(qū)積累，表現(xiàn)出神經(jīng)毒性作用[24]。這一特性依賴于pTh17細胞表達的特殊粘附分子及其分泌的細胞因子。

pTh17細胞能夠以MCAM/MCAM的方式粘附ECs，特異性阻斷MCAM (melanoma cell adhesion molecule)可以限制pTh17細胞的遷移行為并降低EAE的嚴(yán)重程度[25]。趨化因子受體6 (chemokine receptor 6, CCR6)是RORγt/RORc誘導(dǎo)的一種Th17細胞特征性表面分子，其配體CCL20在炎癥部位如脈絡(luò)叢上皮細胞密集表達，兩者之間的相互作用亦參與了pTh17細胞在CNS的浸潤過程[26]。其他的表面粘附分子相互作用對，如ICAM-1/LFA-1 (inter-cellular adhesion molecule-1/lymphocyte function- associated antigen-1)、VCAM-1/VLA-4 (vascular cell adhesion molecule-1/very late antigen-4)、E-selectin/ ESL-1 (E-selectin ligand-1)、ICAM-1/Mac-1 (macro-phage-1 antigen)以及P-selectin/PSGL-1 (P-selectin glycoprotein ligand-1)等，在pTh17細胞粘附BBB緊密連接區(qū)域的ECs方面發(fā)揮作用[27]。

pTh17細胞標(biāo)志性表達的IL-17是其進一步破壞BBB的主要效應(yīng)因子。IL-17可促進IL-6、MIP-2 (macrophage inflammatory protein-2)、NO和黏附分子的產(chǎn)生，促進中性粒細胞浸潤[28]。中性粒細胞分泌基質(zhì)金屬蛋白酶(matrix metalloproteinases, MMPs)、明膠酶和蛋白酶等各種酶類，使BBB的屏障功能進一步瓦解，有助于免疫細胞的順利突破。此外，IL-17增加了CNS中活性氧(reactive oxygen species, ROS)的產(chǎn)生，ROS增多導(dǎo)致ECs黏附分子上調(diào)，促進單核/巨噬細胞等其他炎性細胞向腦實質(zhì)遷移[29]。

2.2 激活膠質(zhì)細胞

增強小膠質(zhì)細胞功能是與IL-17相關(guān)的另一個致病特征[30]。浸潤腦實質(zhì)后，pTh17細胞通過IL-17/IL-17R信號激活小膠質(zhì)細胞，增加其表面共刺激分子(如ICAM-1、CD40、CD80和CD86等)和MHC-II的表達?；罨男∧z質(zhì)細胞分泌IL-1β、TNF-α、IL-6、補體蛋白和ROS等，在神經(jīng)炎癥中起關(guān)鍵作用[31]，其中IL-1β、IL-6和TNF-α (tumor necrosis factor alpha)可啟動神經(jīng)元凋亡通路，最終導(dǎo)致神經(jīng)退行性病變。

血管周圍星形膠質(zhì)細胞是BBB重要的結(jié)構(gòu)和功能組成部分之一，其末端與內(nèi)皮細胞層相互作用，包繞大腦的脈管系統(tǒng)[32]。星形膠質(zhì)細胞表達IL-17R (IL-17 receptor)，IL-17與之結(jié)合后會刺激星形膠質(zhì)細胞向反應(yīng)型表型極化，并產(chǎn)生多種炎癥因子和趨化因子[33,34]。IL-17還促進星形膠質(zhì)細胞表達CCL20[33,35]，從而加速pTh17細胞向CNS遷移。此外，Th17細胞相關(guān)細胞因子上調(diào)腦干星形膠質(zhì)細胞表面VCAM-1的表達，進一步促進CNS內(nèi)炎癥細胞的聚集[36]。

2.3 損傷神經(jīng)元

在神經(jīng)炎癥背景下，pTh17細胞觸發(fā)IL-1β、IL-6和TNF-α等一系列促炎細胞因子的產(chǎn)生，它們與神經(jīng)元表面的受體結(jié)合介導(dǎo)神經(jīng)元凋亡[37]。靶向谷氨酸興奮性毒性是pTh17細胞損傷神經(jīng)元的另一效應(yīng)途徑，主要指向受VCAM-1/integrin β1/KV 1.3信號軸控制的神經(jīng)元[38]。此外，pTh17細胞可以通過細胞間直接接觸的機制誘導(dǎo)神經(jīng)元內(nèi)鈣離子升高，導(dǎo)致軸突腫脹和細胞死亡，亦可通過Fas/FasL相互作用直接誘導(dǎo)神經(jīng)元凋亡[39]。

3 致病性Th17細胞分化的調(diào)控機制

3.1 IL-23

初始CD4+T細胞缺乏IL-23R，因此IL-23并不參與Th17細胞的極化[40]，但在穩(wěn)定和增強Th17細胞表型方面，IL-23具有關(guān)鍵作用。通過誘導(dǎo)IL-23R的表達，IL-23賦予了Th17細胞致病效應(yīng)，通過STAT3機制穩(wěn)定Th17細胞的致病表型。Hirota等[41]的研究表明，pTh17細胞上T-bet和IFN-γ的表達也依賴于IL-23的存在。IL-23/IL-23R信號共同促進Th17細胞的穩(wěn)定和存活，這對于Th17細胞獲得致病特性是必不可少的。IL-23抑制CD5L的表達并調(diào)節(jié)Th17細胞的代謝狀態(tài)，在IL-23下游的轉(zhuǎn)錄因子Blimp-1 (B-lymphocyte-induced maturation protein-1)亦可驅(qū)動pTh17細胞的致病程序，同時抑制pTh17細胞的抑制因子IL-2和Bcl6 (B-cell lymphoma 6)[42]。

血清糖皮質(zhì)激素激酶1 (serum glucocorticoid kinase 1, SGK1)是一種絲氨酸/蘇氨酸激酶，是IL-23信號傳導(dǎo)的一個重要節(jié)點。體外實驗表明，適當(dāng)增加鹽濃度誘導(dǎo)SGK1表達，促進IL-23R表達并增強pTh17細胞分化，從而加速自身免疫疾病的發(fā)展[43]。對EAE動物模型的研究進一步表明，高鹽飲食會加劇疾病嚴(yán)重程度，并伴隨pTh17細胞在脊髓中的浸潤增加[44]。這些數(shù)據(jù)表明SGK1在調(diào)節(jié)IL-23R表達和維持pTh17細胞表型方面具有關(guān)鍵作用，提供了環(huán)境因素(如高鹽飲食)觸發(fā)pTh17細胞發(fā)育并促進組織炎癥的分子機制。

3.2 GM-CSF

在神經(jīng)炎癥中，另一個介導(dǎo)Th17細胞致病性的重要細胞因子是GM-CSF。GM-CSF是一種與自身炎癥相關(guān)的促炎癥細胞因子，它可以促進DCs的成熟以及粒細胞和巨噬細胞的活化，并使髓樣細胞從骨髓動員到外周[45]。pTh17細胞中GM-CSF的增加涉及以下兩種機制：(1) IL-23和RORγt驅(qū)動Th17細胞中GM-CSF的產(chǎn)生[15]；(2) GM-CSF作用于DCs以增強其IL-23的表達，進而促進pTh17細胞的進一步激活和GM-CSF的產(chǎn)生[16]。El-Behi等[46]指出，在中樞神經(jīng)系統(tǒng)自身免疫的背景下，IL-1β和IL-23誘導(dǎo)Th17細胞產(chǎn)生GM-CSF，并且GM-CSF在腦致病性中具有重要作用；缺乏GM-CSF的pTh17細胞，盡管可以產(chǎn)生IL-17和IFN-γ，卻不能導(dǎo)致神經(jīng)炎癥性疾病。

3.3 TGF-β超家族

TGF-β是TGF-β超家族成員之一，包括TGF-β1、TGF-β2和TGF-β3三種亞型[47]，TGF-β相關(guān)信號通路在體內(nèi)和體外對Th17細胞的分化起重要作用[48～50]。T細胞是TGF-β1的重要來源之一，極化后的Th1、Th2和Th17細胞都可以表達TGF-β1，但表達量增加最為明顯的是Th17細胞[51]。初始T細胞分化為Th17細胞有賴于TGF-β1的自分泌[49]，但TGF-β1并不會影響IL-17A的表達，因為從f/fCD4- Cre+小鼠(T細胞中TGFβRI信號被阻斷的小鼠)的腸道中仍可檢測到產(chǎn)生IL-17A的CD4+T細胞[52]。TGF-β不僅促進Th17細胞分化，還參與決定Th17細胞的致病性。與TGF-β1相比，TGF-β3聯(lián)合IL-6誘導(dǎo)的Th17細胞在EAE中具有更強的致病作用[7,52]，且TRIM28 (tripartite motif-containing 28)缺陷引起的TGF-β3過表達會大大促進pTh17細胞的發(fā)育和累積[53]。在TGF-β信號轉(zhuǎn)導(dǎo)通路中，TGF-β超家族成員作為配體與受體結(jié)合后會激活不同的Smad蛋白亞型，從而調(diào)控不同靶基因的特異性表達，這對TGF-β信號轉(zhuǎn)導(dǎo)的最終生物學(xué)效應(yīng)起著決定性作用[54]。雖然TGFβ3與TGFβ1都與TGFβRII (ALK5)結(jié)合，但TGFβ3在pTh17細胞中誘導(dǎo)了Smad1/5的激活，而不是經(jīng)典的Smad2/3信號。這些研究表明，TGFβ3誘導(dǎo)的pTh17細胞從發(fā)育途徑上就不同于non-pTh17細胞。

激活素A (activin-A)是也TGF-β超家族的成員之一，是一種與TGF-β1密切相關(guān)的多效性細胞因子，可以調(diào)節(jié)組織穩(wěn)態(tài)、細胞增殖和組織炎癥[55]。在體外，activin-A可以誘導(dǎo)Th17細胞分化[56]，這一點與TGF-β1類似。但最近的一項研究發(fā)現(xiàn)activin-A和TGF-β1對pTh17細胞的作用截然不同。TGF-β1與ALK5的結(jié)合抑制ERK (extracellular signal-regulated kinase)磷酸化，而activin-A與其受體(AKL4)結(jié)合后激活ERK[57]，ERK磷酸化激活賦予了Th17細胞致病能力[58,59]，因此，內(nèi)源性activin-A/ALK4/ERK通路對于促進pTh17細胞介導(dǎo)的神經(jīng)炎癥的至關(guān)重要。作為調(diào)節(jié)TGF-β/activin-A/Nodal信號傳導(dǎo)的因子，磷酸酶PP2A (protein phosphatase 2A)通過調(diào)控Smad2和Smad3的磷酸化來促進pTh17細胞的產(chǎn)生，并介導(dǎo)EAE效應(yīng)[60]。這些發(fā)現(xiàn)表明，TGF-β超家族通過多種復(fù)雜的分子網(wǎng)絡(luò)在pTh17細胞的產(chǎn)生和功能中發(fā)揮著廣泛的作用。

3.4 MicroRNAs

MicroRNAs (miRNAs)是單鏈、約22 nt的非編碼RNA，是復(fù)雜的基因表達網(wǎng)絡(luò)在轉(zhuǎn)錄后水平上的關(guān)鍵調(diào)控因子，參與包括細胞發(fā)育和分化在內(nèi)的多種生物過程。在271個物種中大約有38,589個miRNA前體，產(chǎn)生48,860個成熟的miRNA[61]。對MS患者T細胞中miRNA圖譜的分析以及眾多基于EAE動物模型的研究表明，miRNAs可能在調(diào)控Th17細胞分化和MS病理生理過程中發(fā)揮重要作用[62,63]。

miR-183C包含miR-183、miR-96和miR-182三種miRNA，受Dicer1調(diào)控，在pTh17細胞中顯著表達，通過抑制FOXO1 (forkhead box protein O1)促進Th17細胞產(chǎn)生致病特性[64]。在Th17極化的初始T細胞中，IL-6通過IL-6/STAT3信號上調(diào)miR-183C表達，其中miR-96可特異性地促進pTh17細胞產(chǎn)生IL-17A、IL-17F、IL-22和GM-CSF等炎癥因子，從而放大pTh17細胞的致病效應(yīng)，使EAE動物的病理評分明顯升高，而TGF-β則下調(diào)miR-183C的表達。miR-448是一種在腫瘤細胞中異常表達的miRNA，廣泛參與增殖、凋亡、侵襲和上皮-間充質(zhì)轉(zhuǎn)化等病理生理過程[65～68]。最近有研究者在MS患者腦脊液和PBMCs (peripheral blood mononuclear cells)中檢測到miR-448的異常表達，且其表達水平與疾病嚴(yán)重程度正相關(guān)。進一步研究EAE小鼠發(fā)現(xiàn)miR-448可上調(diào)IL-17A與RORγt的表達，促進pTh17細胞分化，亦可直接靶向PTPN2 (protein tyrosine phos-phatase non-receptor type 2)，抑制其對Th17細胞分化的抑制作用[69]。與健康對照者相比，miR-20b是MS患者PBMCs中唯一下調(diào)的miRNA[70]，使用慢病毒載體在體內(nèi)過表達miRNA-20b可減少pTh17細胞數(shù)量，降低EAE嚴(yán)重程度，其下游靶點可能是RORγt和STAT3[71]。

3.5 其他調(diào)節(jié)靶點

RNA結(jié)合蛋白HuR是胚胎致死異常視覺(em-bryonic lethal abnormal vision, ELAV)家族的成員，敲除HuR可降低轉(zhuǎn)錄因子RORγt、IRF4 (interferon regulatory factor 4)、RUNX1 (runt-related transcription factor 1)和T-bet的水平，從而減少EAE模型中IL-17+IFN-γ+CD4+T細胞的數(shù)量[72]。另一項研究表明，HuR通過結(jié)合和穩(wěn)定CCR6 mRNA以及促進翻譯來調(diào)節(jié)CCR6的表達，敲除HuR降低了Th17細胞表面的CCR6表達水平，抑制其向CNS的遷移能力，從而改善EAE[73]。這些發(fā)現(xiàn)凸顯了HuR促進Th17細胞介導(dǎo)的自身免疫性神經(jīng)炎癥的分子機制，提示HuR是治療CNS自身免疫性疾病的潛在靶標(biāo)。

Roy等[74]發(fā)現(xiàn)活化的T細胞使用外源性蛋氨酸合成S-腺苷蛋氨酸(S-adenosyl methionine, SAM)，而限制蛋氨酸攝入可降低T細胞內(nèi)SAM和組蛋白H3K4me3 (histone 3 lysine 4 trimethylation)水平，并通過限制pTh17細胞的擴增來改善EAE的發(fā)作和嚴(yán)重程度；該研究證明了限制蛋氨酸飲食能夠通過影響Th17細胞的增殖及其細胞因子的產(chǎn)生來影響T細胞介導(dǎo)的自身免疫。Jonathan等[75]提出E3泛素連接酶Hectd3 (HECT domain-containing E3 ubiquitin ligase 3)對MALT1 (mucosa-associated lymphoid tissue lymphoma translocation 1)和STAT3的非降解性泛素化修飾，分別導(dǎo)致NF-κB (Nuclear factor-κB)活化和RORγt上調(diào)，促進EAE中pTh17細胞分化，且–/–小鼠的EAE癥狀改善與IL-17A和GM-CSF表達降低、RORγt下調(diào)以及–/–CD4+T細胞中STAT3 Y705位點磷酸化的減少相關(guān)，揭示了泛素化影響Th17細胞分化和功能的具體機制。

4 結(jié)語與展望

從2005年首次發(fā)現(xiàn)至今，對于Th17細胞分化、功能和調(diào)控的探索已經(jīng)取得了飛躍式的進展。隨著技術(shù)的不斷革新，對細胞異質(zhì)性的研究手段也從流式細胞技術(shù)[76]和基于細胞群體的基因組圖譜分析進入單細胞測序(single cell RNA sequencing)時代[77]。Gaublomme等[78]在疾病高峰期分離EAE小鼠CNS和引流淋巴結(jié)中的Th17細胞，隨后進行單細胞測序，并與體外分化的pTh17細胞和non-pTh17細胞測序結(jié)果進行比對，結(jié)果顯示Th17細胞的致病性不僅是由于促炎基因()表達上調(diào)，也與免疫抑制基因()的下調(diào)有關(guān)。這些與Th17細胞異質(zhì)性相關(guān)的基因既有已知的調(diào)節(jié)因子，也包括了新的候選基因，且兩種細胞的基因組圖譜的有一定程度的重疊。研究者利用基因敲除小鼠進一步驗證后，篩選出了和四個極具潛力的候選基因[12,76]，希望能夠在不影響non-Th17細胞及機體屏障功能的前提下，約束pTh17細胞的致病能力，延緩神經(jīng)炎癥的發(fā)生發(fā)展。目前仍有許多未知的領(lǐng)域亟待進一步的科學(xué)探索，如pTh17和non-pTh17細胞之間的產(chǎn)生及分化的具體分子機制、如何在病理條件下更明確地區(qū)分二者以及能否逆轉(zhuǎn)pTh17細胞致病性等，而這些謎題的揭秘將有助于未來找尋出更多Th17相關(guān)神經(jīng)炎癥疾病的精準(zhǔn)治療方法。

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Research progress on the role and regulatory mechanism of pathogenic Th17 cells in neuroinflammation

Hongyu Dai1,2, Dong Ji1,2, Cheng Tan1,2, Jie Sun3, Hao Yao1,2

Neuroinflammation is a complex immune response in the central nervous system against various factors such as injury, infection and toxins which interfere with homeostasis, involving a variety of immune cells lingering in the central nervous system. Persistent neuroinflammation is a common denominator of the etiology and course of all neurological diseases, including neurodevelopmental, neurodegenerative and psychiatric disorders, such as Alzheimer’s disease, Parkinson’s disease, multiple sclerosis and depression. Th17 cells, known as an important subtpye of CD4+T cells, mediate immune responses against extracellular bacteria and fungi in steady-state and maintain the defense function of the intestinal mucosal barrier. However, when the cytokine microenvironmentundergoes inflammatory changes, Th17 cells can transform into a highly pro-inflammatory pathogenic phenotype, break through the blood-brain barrier and recruit more inflammatory cells to participate in neuroinflammation, ultimately leading to neurodegeneration. In this review, we summarize the differentiation regulation of pathogenic Th17 cells and their roles in neuroinflammation, which is informative for understanding the interactions between immune system and nervous system.

neuroinflammation; pathogenic Th17 cells; blood-brain barrier; RORγt

2022-02-12;

2022-03-18;

2022-03-25

江蘇省科技廳省級重點研發(fā)計劃(社會發(fā)展)項目(編號：SBE2021741263)和南京醫(yī)科大學(xué)第二附屬醫(yī)院789人才培養(yǎng)計劃(編號：789ZYRC080236)資助[Supported by the Provincial Key R&D Program (Social Development) of Science and Technology Department of Jiangsu Province (No. SBE2021741263), and the 789 Talents Training Program of the Second Affiliated Hospital of Nanjing Medical University (No. 789ZYRC080236)]

戴鴻宇，在讀碩士研究生，專業(yè)方向：麻醉學(xué)。E-mail: daihongyu@njmu.edu.cn

姚昊，博士，副教授，研究方向：圍術(shù)期臟器保護。E-mail: yaohao@njmu.edu.cn

孫杰，博士，副教授，研究方向：麻醉與術(shù)后認(rèn)知功能。E-mail: dgsunjie@hotmail.com

10.16288/j.yczz.22-030

(責(zé)任編委: 何淑君)