戴鴻宇，季東，談程，孫杰，姚昊

致病性Th17細(xì)胞在神經(jīng)炎癥中的作用及調(diào)控機(jī)制的研究進(jìn)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(xì)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(xì)胞是CD4+T細(xì)胞的一個(gè)重要亞型，在穩(wěn)態(tài)條件下介導(dǎo)對(duì)細(xì)胞外細(xì)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(xì)胞因子微環(huán)境發(fā)生炎癥性改變時(shí)，Th17細(xì)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(duì)致病性Th17細(xì)胞的分化調(diào)控及其在神經(jīng)炎癥中的作用進(jìn)行了系統(tǒng)綜述，對(duì)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(xì)胞；血腦屏障；RORγt

炎癥是機(jī)體對(duì)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(guò)激或趨于慢性時(shí)，會(huì)形成炎癥環(huán)境，免疫系統(tǒng)轉(zhuǎn)而攻擊自身組織和細(xì)胞，導(dǎo)致進(jìn)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(xì)胞和多種駐留細(xì)胞，包括膠質(zhì)細(xì)胞(小膠質(zhì)細(xì)胞、星形膠質(zhì)細(xì)胞、少突膠質(zhì)細(xì)胞)、髓樣細(xì)胞(巨噬細(xì)胞和樹(shù)突狀細(xì)胞)以及外周白細(xì)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(xì)胞介導(dǎo)的免疫反應(yīng)之間存在相關(guān)性[2]。Th17細(xì)胞作為已證實(shí)的致病細(xì)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(duì)致病性Th17細(xì)胞的分化調(diào)控及其在神經(jīng)炎癥中的作用進(jìn)行了系統(tǒng)綜述，深入闡述了致病性Th17細(xì)胞的產(chǎn)生和致病性的分子調(diào)控機(jī)制，對(duì)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(jìn)展具有一定參考意義。

1 Th17細(xì)胞概況

Th17細(xì)胞是一類(lèi)獨(dú)立于Th1和Th2的CD4+T細(xì)胞亞型，產(chǎn)生標(biāo)志性細(xì)胞因子IL-17，特異性表達(dá)維甲酸相關(guān)孤兒受體γt (retinoic acid-associated orphan receptor gamma t, RORγt)和信號(hào)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(lái)Th17細(xì)胞引起了人們的極大關(guān)注[5]。在穩(wěn)態(tài)條件下，Th17細(xì)胞介導(dǎo)對(duì)細(xì)胞外細(xì)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(xì)胞因子微環(huán)境發(fā)生炎癥性改變時(shí)，Th17細(xì)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(xì)胞參與神經(jīng)炎癥，導(dǎo)致神經(jīng)變性。鑒于Th17細(xì)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(xì)胞對(duì)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(xì)胞因子微環(huán)境[7]。鑒于此，越來(lái)越多的研究致力于揭示Th17細(xì)胞的異質(zhì)性及其調(diào)控機(jī)制。

1.1 Th17細(xì)胞的異質(zhì)性

Th17細(xì)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(xì)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(guò)繼轉(zhuǎn)移后是否具有誘導(dǎo)實(shí)驗(yàn)性自身免疫性腦脊髓膜炎(experimental autoimmune encephalomyelitis, EAE)的能力，可將Th17細(xì)胞分為致病性Th17細(xì)胞(pathogenic Th17 cells, pTh17 cells)和非致病性Th17細(xì)胞(non-pathogenic Th17 cells, non-pTh17 cells)兩種表型[9]。

1.2 非致病性Th17細(xì)胞的產(chǎn)生與功能

轉(zhuǎn)化生長(zhǎng)因子β1 (transforming growth factor beta 1, TGF-β1)和IL-6誘導(dǎo)的Th17細(xì)胞多數(shù)情況下被認(rèn)為是non-pTh17細(xì)胞(圖1)，甚至在某些腸道疾病中表現(xiàn)出保護(hù)作用[10,11]。它表達(dá)免疫調(diào)節(jié)細(xì)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(fù)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(xì)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(lài)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(xì)胞中特異性上調(diào)，通過(guò)限制其膽固醇衍生配體的獲取來(lái)抑制RORγt的轉(zhuǎn)錄活性[9]。

圖1 Th17細(xì)胞分化途徑、信號(hào)轉(zhuǎn)導(dǎo)因子及細(xì)胞因子示意圖

TGF-β1聯(lián)合IL-6有助于Th17細(xì)胞的極化，而IL-1β、IL-6、IL-23、TGF-β3的加入使Th17細(xì)胞進(jìn)一步分化為致病性Th17細(xì)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(xiàn)[9]，使用BioRender.com修改繪制。

1.3 致病性Th17細(xì)胞的產(chǎn)生與功能

在抗原呈遞細(xì)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(xì)胞[14]，這表明IL-23/IL-23R通路在pTh17細(xì)胞誘導(dǎo)炎癥反應(yīng)中起著重要作用，缺乏IL-23R (IL-23 receptor)會(huì)降低pTh17細(xì)胞的致病潛能，并減少其在CNS的聚集。pTh17細(xì)胞在CNS中的致病性一方面有賴(lài)于其高度表達(dá)的粒細(xì)胞巨噬細(xì)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(guò)作用于樹(shù)突狀細(xì)胞(dendritic cells, DCs)提高pTh17細(xì)胞IL-23的產(chǎn)量[16]，從而形成一個(gè)正反饋回路。另一方面，pTh17細(xì)胞兼有Th17和Th1細(xì)胞的促炎特性和致病特征，可同時(shí)分泌IL-17和IFN-γ (Th1的標(biāo)志性細(xì)胞因子)，且共同表達(dá)轉(zhuǎn)錄因子RORγt/RORC [小鼠()/人類(lèi)()]和T-bet (T-box expressed in T cells，Th1細(xì)胞的特異性轉(zhuǎn)錄因子)，因此亦被命名為T(mén)h17.1細(xì)胞[17]。

與non-p17細(xì)胞相比，具有強(qiáng)烈Th1傾向性的pTh17細(xì)胞具有更強(qiáng)的破壞BBB的能力，使炎癥細(xì)胞更易于向CNS浸潤(rùn)[18]。激活后的pTh17細(xì)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(dá)，而MDR1能潛在地保護(hù)pTh17細(xì)胞免受治療藥物的影響[19]。此外，pTh17細(xì)胞對(duì)Tregs (regulatory T cells)的抑制可能有一定的抵抗力[20]?？偟膩?lái)說(shuō)，pTh17細(xì)胞具有一些典型的炎癥細(xì)胞特征，這使它們?cè)贑NS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(jī)制

pTh17細(xì)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(shí)，而pTh17細(xì)胞衍生的細(xì)胞因子亦可直接或間接地增強(qiáng)中樞神經(jīng)系統(tǒng)的炎癥反應(yīng)[21]。pTh17細(xì)胞誘導(dǎo)并參與神經(jīng)炎癥的相關(guān)機(jī)制主要包括如下方面(圖2)。

圖2 致病性Th17細(xì)胞參與神經(jīng)炎癥的分子機(jī)制示意圖

外周血中的pTh17細(xì)胞通過(guò)產(chǎn)生促炎細(xì)胞因子和細(xì)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(xì)胞和促炎介質(zhì)涌入CNS，進(jìn)一步破壞BBB。在CNS中，pTh17細(xì)胞的浸潤(rùn)激活小膠質(zhì)細(xì)胞，IL-17/IL-17R信號(hào)決定其炎癥因子的表達(dá)，并增加ROS的產(chǎn)生，促進(jìn)中性粒細(xì)胞的趨化和聚集?；罨男∧z質(zhì)細(xì)胞啟動(dòng)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(xiàn)[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(xì)胞進(jìn)入腦實(shí)質(zhì)，并為CNS提供氧氣和關(guān)鍵營(yíng)養(yǎng)物質(zhì)。高度特化的內(nèi)皮細(xì)胞(endothelial cells, ECs)通過(guò)與周細(xì)胞、血管周?chē)切文z質(zhì)細(xì)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(xì)胞和溶質(zhì)的細(xì)胞旁和跨細(xì)胞運(yùn)動(dòng)，確保了BBB的功能性和完整性[22,23]。穿越BBB是pTh17細(xì)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(xì)胞能夠優(yōu)先穿越人類(lèi)的BBB，且在EAE小鼠和MS患者的腦實(shí)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(lài)于pTh17細(xì)胞表達(dá)的特殊粘附分子及其分泌的細(xì)胞因子。

pTh17細(xì)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(xì)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(xì)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(xì)胞密集表達(dá)，兩者之間的相互作用亦參與了pTh17細(xì)胞在CNS的浸潤(rùn)過(guò)程[26]。其他的表面粘附分子相互作用對(duì)，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(xì)胞粘附BBB緊密連接區(qū)域的ECs方面發(fā)揮作用[27]。

pTh17細(xì)胞標(biāo)志性表達(dá)的IL-17是其進(jìn)一步破壞BBB的主要效應(yīng)因子。IL-17可促進(jìn)IL-6、MIP-2 (macrophage inflammatory protein-2)、NO和黏附分子的產(chǎn)生，促進(jìn)中性粒細(xì)胞浸潤(rùn)[28]。中性粒細(xì)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(lèi)，使BBB的屏障功能進(jìn)一步瓦解，有助于免疫細(xì)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(jìn)單核/巨噬細(xì)胞等其他炎性細(xì)胞向腦實(shí)質(zhì)遷移[29]。

2.2 激活膠質(zhì)細(xì)胞

增強(qiáng)小膠質(zhì)細(xì)胞功能是與IL-17相關(guān)的另一個(gè)致病特征[30]。浸潤(rùn)腦實(shí)質(zhì)后，pTh17細(xì)胞通過(guò)IL-17/IL-17R信號(hào)激活小膠質(zhì)細(xì)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(dá)?；罨男∧z質(zhì)細(xì)胞分泌IL-1β、TNF-α、IL-6、補(bǔ)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(dòng)神經(jīng)元凋亡通路，最終導(dǎo)致神經(jīng)退行性病變。

血管周?chē)切文z質(zhì)細(xì)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(xì)胞層相互作用，包繞大腦的脈管系統(tǒng)[32]。星形膠質(zhì)細(xì)胞表達(dá)IL-17R (IL-17 receptor)，IL-17與之結(jié)合后會(huì)刺激星形膠質(zhì)細(xì)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(jìn)星形膠質(zhì)細(xì)胞表達(dá)CCL20[33,35]，從而加速pTh17細(xì)胞向CNS遷移。此外，Th17細(xì)胞相關(guān)細(xì)胞因子上調(diào)腦干星形膠質(zhì)細(xì)胞表面VCAM-1的表達(dá)，進(jìn)一步促進(jìn)CNS內(nèi)炎癥細(xì)胞的聚集[36]。

2.3 損傷神經(jīng)元

在神經(jīng)炎癥背景下，pTh17細(xì)胞觸發(fā)IL-1β、IL-6和TNF-α等一系列促炎細(xì)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(xì)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(hào)軸控制的神經(jīng)元[38]。此外，pTh17細(xì)胞可以通過(guò)細(xì)胞間直接接觸的機(jī)制誘導(dǎo)神經(jīng)元內(nèi)鈣離子升高，導(dǎo)致軸突腫脹和細(xì)胞死亡，亦可通過(guò)Fas/FasL相互作用直接誘導(dǎo)神經(jīng)元凋亡[39]。

3 致病性Th17細(xì)胞分化的調(diào)控機(jī)制

3.1 IL-23

初始CD4+T細(xì)胞缺乏IL-23R，因此IL-23并不參與Th17細(xì)胞的極化[40]，但在穩(wěn)定和增強(qiáng)Th17細(xì)胞表型方面，IL-23具有關(guān)鍵作用。通過(guò)誘導(dǎo)IL-23R的表達(dá)，IL-23賦予了Th17細(xì)胞致病效應(yīng)，通過(guò)STAT3機(jī)制穩(wěn)定Th17細(xì)胞的致病表型。Hirota等[41]的研究表明，pTh17細(xì)胞上T-bet和IFN-γ的表達(dá)也依賴(lài)于IL-23的存在。IL-23/IL-23R信號(hào)共同促進(jìn)Th17細(xì)胞的穩(wěn)定和存活，這對(duì)于Th17細(xì)胞獲得致病特性是必不可少的。IL-23抑制CD5L的表達(dá)并調(diào)節(jié)Th17細(xì)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(dòng)pTh17細(xì)胞的致病程序，同時(shí)抑制pTh17細(xì)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(hào)傳導(dǎo)的一個(gè)重要節(jié)點(diǎn)。體外實(shí)驗(yàn)表明，適當(dāng)增加鹽濃度誘導(dǎo)SGK1表達(dá)，促進(jìn)IL-23R表達(dá)并增強(qiáng)pTh17細(xì)胞分化，從而加速自身免疫疾病的發(fā)展[43]。對(duì)EAE動(dòng)物模型的研究進(jìn)一步表明，高鹽飲食會(huì)加劇疾病嚴(yán)重程度，并伴隨pTh17細(xì)胞在脊髓中的浸潤(rùn)增加[44]。這些數(shù)據(jù)表明SGK1在調(diào)節(jié)IL-23R表達(dá)和維持pTh17細(xì)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(xì)胞發(fā)育并促進(jìn)組織炎癥的分子機(jī)制。

3.2 GM-CSF

在神經(jīng)炎癥中，另一個(gè)介導(dǎo)Th17細(xì)胞致病性的重要細(xì)胞因子是GM-CSF。GM-CSF是一種與自身炎癥相關(guān)的促炎癥細(xì)胞因子，它可以促進(jìn)DCs的成熟以及粒細(xì)胞和巨噬細(xì)胞的活化，并使髓樣細(xì)胞從骨髓動(dòng)員到外周[45]。pTh17細(xì)胞中GM-CSF的增加涉及以下兩種機(jī)制：(1) IL-23和RORγt驅(qū)動(dòng)Th17細(xì)胞中GM-CSF的產(chǎn)生[15]；(2) GM-CSF作用于DCs以增強(qiáng)其IL-23的表達(dá)，進(jìn)而促進(jìn)pTh17細(xì)胞的進(jìn)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(xì)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(xì)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(hào)通路在體內(nèi)和體外對(duì)Th17細(xì)胞的分化起重要作用[48～50]。T細(xì)胞是TGF-β1的重要來(lái)源之一，極化后的Th1、Th2和Th17細(xì)胞都可以表達(dá)TGF-β1，但表達(dá)量增加最為明顯的是Th17細(xì)胞[51]。初始T細(xì)胞分化為T(mén)h17細(xì)胞有賴(lài)于TGF-β1的自分泌[49]，但TGF-β1并不會(huì)影響IL-17A的表達(dá)，因?yàn)閺膄/fCD4- Cre+小鼠(T細(xì)胞中TGFβRI信號(hào)被阻斷的小鼠)的腸道中仍可檢測(cè)到產(chǎn)生IL-17A的CD4+T細(xì)胞[52]。TGF-β不僅促進(jìn)Th17細(xì)胞分化，還參與決定Th17細(xì)胞的致病性。與TGF-β1相比，TGF-β3聯(lián)合IL-6誘導(dǎo)的Th17細(xì)胞在EAE中具有更強(qiáng)的致病作用[7,52]，且TRIM28 (tripartite motif-containing 28)缺陷引起的TGF-β3過(guò)表達(dá)會(huì)大大促進(jìn)pTh17細(xì)胞的發(fā)育和累積[53]。在TGF-β信號(hào)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(huì)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(dá)，這對(duì)TGF-β信號(hào)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(xì)胞中誘導(dǎo)了Smad1/5的激活，而不是經(jīng)典的Smad2/3信號(hào)。這些研究表明，TGFβ3誘導(dǎo)的pTh17細(xì)胞從發(fā)育途徑上就不同于non-pTh17細(xì)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(xì)胞因子，可以調(diào)節(jié)組織穩(wěn)態(tài)、細(xì)胞增殖和組織炎癥[55]。在體外，activin-A可以誘導(dǎo)Th17細(xì)胞分化[56]，這一點(diǎn)與TGF-β1類(lèi)似。但最近的一項(xiàng)研究發(fā)現(xiàn)activin-A和TGF-β1對(duì)pTh17細(xì)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(xì)胞致病能力[58,59]，因此，內(nèi)源性activin-A/ALK4/ERK通路對(duì)于促進(jìn)pTh17細(xì)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(hào)傳導(dǎo)的因子，磷酸酶PP2A (protein phosphatase 2A)通過(guò)調(diào)控Smad2和Smad3的磷酸化來(lái)促進(jìn)pTh17細(xì)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(guò)多種復(fù)雜的分子網(wǎng)絡(luò)在pTh17細(xì)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(dá)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(xì)胞發(fā)育和分化在內(nèi)的多種生物過(guò)程。在271個(gè)物種中大約有38,589個(gè)miRNA前體，產(chǎn)生48,860個(gè)成熟的miRNA[61]。對(duì)MS患者T細(xì)胞中miRNA圖譜的分析以及眾多基于EAE動(dòng)物模型的研究表明，miRNAs可能在調(diào)控Th17細(xì)胞分化和MS病理生理過(guò)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(xì)胞中顯著表達(dá)，通過(guò)抑制FOXO1 (forkhead box protein O1)促進(jìn)Th17細(xì)胞產(chǎn)生致病特性[64]。在Th17極化的初始T細(xì)胞中，IL-6通過(guò)IL-6/STAT3信號(hào)上調(diào)miR-183C表達(dá)，其中miR-96可特異性地促進(jìn)pTh17細(xì)胞產(chǎn)生IL-17A、IL-17F、IL-22和GM-CSF等炎癥因子，從而放大pTh17細(xì)胞的致病效應(yīng)，使EAE動(dòng)物的病理評(píng)分明顯升高，而TGF-β則下調(diào)miR-183C的表達(dá)。miR-448是一種在腫瘤細(xì)胞中異常表達(dá)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(guò)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(cè)到miR-448的異常表達(dá)，且其表達(dá)水平與疾病嚴(yán)重程度正相關(guān)。進(jìn)一步研究EAE小鼠發(fā)現(xiàn)miR-448可上調(diào)IL-17A與RORγt的表達(dá)，促進(jìn)pTh17細(xì)胞分化，亦可直接靶向PTPN2 (protein tyrosine phos-phatase non-receptor type 2)，抑制其對(duì)Th17細(xì)胞分化的抑制作用[69]。與健康對(duì)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(guò)表達(dá)miRNA-20b可減少pTh17細(xì)胞數(shù)量，降低EAE嚴(yán)重程度，其下游靶點(diǎn)可能是RORγt和STAT3[71]。

3.5 其他調(diào)節(jié)靶點(diǎn)

RNA結(jié)合蛋白HuR是胚胎致死異常視覺(jué)(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(xì)胞的數(shù)量[72]。另一項(xiàng)研究表明，HuR通過(guò)結(jié)合和穩(wěn)定CCR6 mRNA以及促進(jìn)翻譯來(lái)調(diào)節(jié)CCR6的表達(dá)，敲除HuR降低了Th17細(xì)胞表面的CCR6表達(dá)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(jìn)Th17細(xì)胞介導(dǎo)的自身免疫性神經(jīng)炎癥的分子機(jī)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(xì)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(xì)胞內(nèi)SAM和組蛋白H3K4me3 (histone 3 lysine 4 trimethylation)水平，并通過(guò)限制pTh17細(xì)胞的擴(kuò)增來(lái)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(guò)影響Th17細(xì)胞的增殖及其細(xì)胞因子的產(chǎn)生來(lái)影響T細(xì)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(duì)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(jìn)EAE中pTh17細(xì)胞分化，且–/–小鼠的EAE癥狀改善與IL-17A和GM-CSF表達(dá)降低、RORγt下調(diào)以及–/–CD4+T細(xì)胞中STAT3 Y705位點(diǎn)磷酸化的減少相關(guān)，揭示了泛素化影響Th17細(xì)胞分化和功能的具體機(jī)制。

4 結(jié)語(yǔ)與展望

從2005年首次發(fā)現(xiàn)至今，對(duì)于Th17細(xì)胞分化、功能和調(diào)控的探索已經(jīng)取得了飛躍式的進(jìn)展。隨著技術(shù)的不斷革新，對(duì)細(xì)胞異質(zhì)性的研究手段也從流式細(xì)胞技術(shù)[76]和基于細(xì)胞群體的基因組圖譜分析進(jìn)入單細(xì)胞測(cè)序(single cell RNA sequencing)時(shí)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(xì)胞，隨后進(jìn)行單細(xì)胞測(cè)序，并與體外分化的pTh17細(xì)胞和non-pTh17細(xì)胞測(cè)序結(jié)果進(jìn)行比對(duì)，結(jié)果顯示Th17細(xì)胞的致病性不僅是由于促炎基因()表達(dá)上調(diào)，也與免疫抑制基因()的下調(diào)有關(guān)。這些與Th17細(xì)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(xì)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(jìn)一步驗(yàn)證后，篩選出了和四個(gè)極具潛力的候選基因[12,76]，希望能夠在不影響non-Th17細(xì)胞及機(jī)體屏障功能的前提下，約束pTh17細(xì)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(jìn)一步的科學(xué)探索，如pTh17和non-pTh17細(xì)胞之間的產(chǎn)生及分化的具體分子機(jī)制、如何在病理?xiàng)l件下更明確地區(qū)分二者以及能否逆轉(zhuǎn)pTh17細(xì)胞致病性等，而這些謎題的揭秘將有助于未來(lái)找尋出更多Th17相關(guān)神經(jīng)炎癥疾病的精準(zhǔn)治療方法。

[1] Solleiro-Villavicencio H, Rivas-Arancibia S. Effect of chronic oxidative stress on neuroinflammatory response mediated by CD4+T cells in neurodegenerative diseases., 2018, 12: 114.

[2] Singh RP, Hasan S, Sharma S, Nagra S, Yamaguchi DT, Wong DTW, Hahn BH, Hossain A. Th17 cells in inflammation and autoimmunity., 2014, 13(12): 1174–1181.

[3] Moser T, Akgün K, Proschmann U, Sellner J, Ziemssen T. The role of TH17 cells in multiple sclerosis: therapeutic implications., 2020, 19(10): 102647.

[4] MacMahon Copas AN, McComish SF, Fletcher JM, Caldwell MA. The pathogenesis of Parkinson’s disease: a complex interplay between astrocytes, microglia, and T lymphocytes?, 2021, 12: 666737.

[5] Harrington LE, Hatton RD, Mangan PR, Turner H, Murphy TL, Murphy KM, Weaver CT. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages., 2005, 6(11): 1123–1132.

[6] Omenetti S, Bussi C, Metidji A, Iseppon A, Lee S, Tolaini M, Li Y, Kelly G, Chakravarty P, Shoaie S, Gutierrez MG, Stockinger B. The intestine harbors functionally distinct homeostatic tissue-resident and inflammatory Th17 cells., 2019, 51(1): 77–89.e6.

[7] Lee Y, Awasthi A, Yosef N, Quintana FJ, Xiao S, Peters A, Wu C, Kleinewietfeld M, Kunder S, Hafler DA, Sobel RA, Regev A, Kuchroo VK. Induction and molecular signature of pathogenic TH17 cells., 2012, 13(10): 991–999.

[8] Ghoreschi K, Laurence A, Yang XP, Hirahara K, O’Shea JJ. T helper 17 cell heterogeneity and pathogenicity in autoimmune disease., 2011, 32(9): 395–401.

[9] Stockinger B, Omenetti S. The dichotomous nature of T helper 17 cells., 2017, 17(9): 535–544.

[10] Dankers W, Davelaar N, van Hamburg JP, van de Peppel J, Colin EM, Lubberts E. Human memory Th17 cell populations change into anti-inflammatory cells with regulatory capacity upon exposure to active vitamin D., 2019, 10: 1504.

[11] O'Connor W, Kamanaka M, Booth CJ, Town T, Nakae S, Iwakura Y, Kolls JK, Flavell RA. A protective function for interleukin 17A in T cell-mediated intestinal inflammation., 2009, 10(6): 603–609.

[12] Wang C, Yosef N, Gaublomme J, Wu C, Lee Y, Clish CB, Kaminski J, Xiao S, Meyer Zu Horste G, Pawlak M, Kishi Y, Joller N, Karwacz K, Zhu C, Ordovas-Montanes M, Madi A, Wortman I, Miyazaki T, Sobel RA, Park H, Regev A, Kuchroo VK. CD5L/AIM regulates lipid biosynthesis and restrains Th17 cell pathogenicity., 2015, 163(6): 1413–1427.

[13] Aschenbrenner D, Foglierini M, Jarrossay D, Hu D, Weiner HL, Kuchroo VK, Lanzavecchia A, Notarbartolo S, Sallusto F. An immunoregulatory and tissue-residency program modulated by c-MAF in human TH17 cells., 2018, 19(10): 1126–1136.

[14] McGeachy MJ, Bak-Jensen KS, Chen Y, Tato CM, Blumenschein W, McClanahan T, Cua DJ. TGF-β and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain T(H)-17 cell-mediated pathology., 2007, 8(12): 1390–1397.

[15] Codarri L, Gyülvészi G, Tosevski V, Hesske L, Fontana A, Magnenat L, Suter T, Becher B. RORγt drives production of the cytokine GM-CSF in helper T cells, which is essential for the effector phase of autoimmune neuroin-flammation., 2011, 12(6): 560–567.

[16] Sonderegger I, Iezzi G, Maier R, Schmitz N, Kurrer M, Kopf M. GM-CSF mediates autoimmunity by enhancing IL-6-dependent Th17 cell development and survival., 2008, 205(10): 2281–2294.

[17] Duhen R, Glatigny S, Arbelaez CA, Blair TC, Oukka M, Bettelli E. Cutting edge: the pathogenicity of IFN-γ- producing Th17 cells is independent of T-bet., 2013, 190(9): 4478–4482.

[18] van Langelaar J, van der Vuurst de Vries RM, Janssen M, Wierenga-Wolf AF, Spilt IM, Siepman TA, Dankers W, Verjans GMGM, de Vries HE, Lubberts E, Hintzen RQ, van Luijn MM. T helper 17.1 cells associate with multiple sclerosis disease activity: perspectives for early intervention., 2018, 141(5): 1334–1349.

[19] Paulissen SMJ, van Hamburg JP, Dankers W, Lubberts E. The role and modulation of CCR6+Th17 cell populations in rheumatoid arthritis., 2015, 74(1): 43–53.

[20] Basdeo SA, Cluxton D, Sulaimani J, Moran B, Canavan M, Orr C, Veale DJ, Fearon U, Fletcher JM. Ex-Th17 (nonclassical th1) cells are functionally distinct from classical Th1 and Th17 cells and are not constrained by regulatory T cells., 2017, 198(6): 2249–2259.

[21] Tahmasebinia F, Pourgholaminejad A. The role of Th17 cells in auto-inflammatory neurological disorders., 2017, 79(Pt B): 408–416.

[22] Mastorakos P, McGavern D. The anatomy and immuno-logy of vasculature in the central nervous system., 2019, 4(37): eaav0492.

[23] Profaci CP, Munji RN, Pulido RS, Daneman R. The blood- brain barrier in health and disease: important unanswered questions., 2020, 217(4): e20190062.

[24] Baumjohann D, Ansel KM. MicroRNA-mediated regulation of T helper cell differentiation and plasticity., 2013, 13(9): 666–678.

[25] Breuer J, Korpos E, Hannocks MJ, Schneider-Hohendorf T, Song J, Zondler L, Herich S, Flanagan K, Korn T, Zarbock A, Kuhlmann T, Sorokin L, Wiendl H, Schwab N. Blockade of MCAM/CD146 impedes CNS infiltration of T cells over the choroid plexus., 2018, 15(1): 236.

[26] Cipollini V, Anrather J, Orzi F, Iadecola C. Th17 and cognitive impairment: possible mechanisms of action., 2019, 13: 95.

[27] Haqqani AS, Stanimirovic DB. Intercellular interactomics of human brain endothelial cells and th17 lymphocytes: a novel strategy for identifying therapeutic targets of CNS inflammation., 2011, 2011: 175364.

[28] Witowski J, Pawlaczyk K, Breborowicz A, Scheuren A, Kuzlan-Pawlaczyk M, Wisniewska J, Polubinska A, Friess H, Gahl GM, Frei U, J?rres A. IL-17 stimulates intraperi-toneal neutrophil infiltration through the release of GRO alpha chemokine from mesothelial cells., 2000, 165(10): 5814–5821.

[29] Huppert J, Closhen D, Croxford A, White R, Kulig P, Pietrowski E, Bechmann I, Becher B, Luhmann HJ, Waisman A, Kuhlmann CRW. Cellular mechanisms of IL-17-induced blood-brain barrier disruption., 2010, 24(4): 1023–1034.

[30] Kawanokuchi J, Shimizu K, Nitta A, Yamada K, Mizuno T, Takeuchi H, Suzumura A. Production and functions of IL-17 in microglia., 2008, 194(1–2): 54–61.

[31] Debnath M, Berk M. Th17 pathway-mediated immuno-pathogenesis of schizophrenia: mechanisms and implica-tions., 2014, 40(6): 1412–1421.

[32] Michinaga S, Koyama Y. Dual roles of astrocyte-derived factors in regulation of blood-brain barrier function after brain damage., 2019, 20(3): 571.

[33] Meares GP, Ma XY, Qin HW, Benveniste EN. Regulation of CCL20 expression in astrocytes by IL-6 and IL-17., 2012, 60(5): 771–781.

[34] Das Sarma J, Ciric B, Marek R, Sadhukhan S, Caruso ML, Shafagh J, Fitzgerald DC, Shindler KS, Rostami A. Functional interleukin-17 receptor A is expressed in central nervous system glia and upregulated in experimental autoimmune encephalomyelitis., 2009, 6: 14.

[35] Kang ZZ, Altuntas CZ, Gulen MF, Liu CN, Giltiay N, Qin HW, Liu LP, Qian W, Ransohoff RM, Bergmann C, Stohlman S, Tuohy VK, Li XX. Astrocyte-restricted ablation of interleukin-17-induced Act1-mediated signaling ameliorates autoimmune encephalomyelitis., 2010, 32(3): 414–425.

[36] Williams JL, Manivasagam S, Smith BC, Sim J, Vollmer LL, Daniels BP, Russell JH, Klein RS. Astrocyte-T cell crosstalk regulates region-specific neuroinflammation., 2020, 68(7): 1361–1374.

[37] Tzartos JS, Craner MJ, Friese MA, Jakobsen KB, Newcombe J, Esiri MM, Fugger L. IL-21 and IL-21 receptor expression in lymphocytes and neurons in multiple sclerosis brain., 2011, 178(2): 794–802.

[38] Birkner K, Wasser B, Ruck T, Thalman C, Luchtman D, Pape K, Schmaul S, Bitar L, Kr?mer-Albers EM, Stroh A, Meuth SG, Zipp F, Bittner S. β1-Integrin- and KV1.3 channel-dependent signaling stimulates glutamate release from Th17 cells., 2020, 130(2): 715–732.

[39] Williams PR, Marincu BN, Sorbara CD, Mahler CF, Schumacher AM, Griesbeck O, Kerschensteiner M, Misgeld T. A recoverable state of axon injury persists for hours after spinal cord contusion in vivo., 2014, 5: 5683.

[40] Wu B, Wan YS. Molecular control of pathogenic Th17 cells in autoimmune diseases., 2020, 80: 106187.

[41] Hirota K, Duarte JH, Veldhoen M, Hornsby E, Li Y, Cua DJ, Ahlfors H, Wilhelm C, Tolaini M, Menzel U, Garefalaki A, Potocnik AJ, Stockinger B. Fate mapping of IL-17-producing T cells in inflammatory responses., 2011, 12(3): 255–263.

[42] Jain R, Chen Y, Kanno Y, Joyce-Shaikh B, Vahedi G, Hirahara K, Blumenschein WM, Sukumar S, Haines CJ, Sadekova S, McClanahan TK, McGeachy MJ, O'Shea JJ, Cua DJ. Interleukin-23-induced transcription factor Blimp-1 promotes pathogenicity of T helper 17 cells., 2016, 44(1): 131–142.

[43] Wu C, Yosef N, Thalhamer T, Zhu C, Xiao S, Kishi Y, Regev A, Kuchroo VK. Induction of pathogenic TH17 cells by inducible salt-sensing kinase SGK1., 2013, 496(7446): 513–517.

[44] Haase S, Wilck N, Kleinewietfeld M, Müller DN, Linker RA. Sodium chloride triggers Th17 mediated autoimmunity., 2019, 329: 9–13.

[45] Fleetwood AJ, Cook AD, Hamilton JA. Functions of granulocyte-macrophage colony-stimulating factor., 2005, 25(5): 405–428.

[46] El-Behi M, Ciric B, Dai H, Yan YP, Cullimore M, Safavi F, Zhang GX, Dittel BN, Rostami A. The encephalitogenicity of T(H)17 cells is dependent on IL-1- and IL-23-induced production of the cytokine GM-CSF., 2011, 12(6): 568–575.

[47] Fujio K, Komai T, Inoue M, Morita K, Okamura T, Yamamoto K. Revisiting the regulatory roles of the TGF-β family of cytokines., 20 16, 15(9): 917– 922.

[48] Bettelli E, Carrier Y, Gao WD, Korn T, Strom TB, Oukka M, Weiner HL, Kuchroo VK. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells., 2006, 441(7090): 235–238.

[49] Gutcher I, Donkor MK, Ma Q, Rudensky AY, Flavell RA, Li MO. Autocrine transforming growth factor-β1 promotes in vivo Th17 cell differentiation., 2011, 34(3): 396–408.

[50] Mangan PR, Harrington LE, O'Quinn DB, Helms WS, Bullard DC, Elson CO, Hatton RD, Wahl SM, Schoeb TR, Weaver CT. Transforming growth factor-beta induces development of the T(H)17 lineage., 2006, 441(7090): 231–234.

[51] Li MO, Wan YY, Flavell RA. T cell-produced transfor-ming growth factor-beta1 controls T cell tolerance and regulates Th1- and Th17-cell differentiation., 2007, 26(5): 579–591.

[52] Ghoreschi K, Laurence A, Yang XP, Tato CM, McGeachy MJ, Konkel JE, Ramos HL, Wei L, Davidson TS, Bouladoux N, Grainger JR, Chen Q, Kanno Y, Watford WT, Sun HW, Eberl G, Shevach EM, Belkaid Y, Cua DJ, Chen WJ, O'Shea JJ. Generation of pathogenic T(H)17 cells in the absence of TGF-β signalling., 2010, 467(7318): 967–971.

[53] Chikuma S, Suita N, Okazaki IM, Shibayama S, Honjo T. TRIM28 prevents autoinflammatory T cell development in vivo., 2012, 13(6): 596–603.

[54] Wang HX, Zhu DH. Functions of smad and its binding proteins in TGF β signal pathway., 2003, 25(4): 479–483.

王海霞, 朱大海. Smad及其結(jié)合蛋白在TGF β信號(hào)傳導(dǎo)中的功能. 遺傳, 2003, 25(4): 479–483.

[55] Morianos I, Papadopoulou G, Semitekolou M, Xanthou G. Activin-A in the regulation of immunity in health and disease., 2019, 104: 102314.

[56] Zhang S, Takaku M, Zou LY, Gu AD, Chou WC, Zhang G, Wu B, Kong Q, Thomas SY, Serody JS, Chen X, Xu XJ, Wade PA, Cook DN, Ting JPY, Wan YY. Reversing SKI-SMAD4-mediated suppression is essential for TH17 cell differentiation., 2017, 551(7678): 105–109.

[57] Wu B, Zhang S, Guo ZL, Bi YM, Zhou MX, Li P, Seyedsadr M, Xu XJ, Li JL, Markovic-Plese S, Wan YY. The TGF-β superfamily cytokine activin-A is induced during autoimmune neuroinflammation and drives patho-genic Th17 cell differentiation., 2021, 54(2): 308–323.e6.

[58] Liu HP, Yao SX, Dann SM, Qin HW, Elson CO, Cong YZ. ERK differentially regulates Th17- and Treg-cell development and contributes to the pathogenesis of colitis., 2013, 43(7): 1716–1726.

[59] Brereton CF, Sutton CE, Lalor SJ, Lavelle EC, Mills KHG. Inhibition of ERK MAPK suppresses IL-23- and IL-1- driven IL-17 production and attenuates autoimmune disease., 2009, 183(3): 1715–1723.

[60] Xu Q, Jin XX, Zheng MZ, Rohila D, Fu GT, Wen ZY, Lou J, Wu SQ, Sloan R, Wang L, Hu H, Gao X, Lu LR. Phosphatase PP2A is essential for TH17 differentiation., 2019, 116(3): 982–987.

[61] Kozomara A, Birgaoanu M, Griffiths-Jones S. miRBase: from microRNA sequences to function., 2019, 47(D1): D155–D162.

[62] Baumjohann D, Ansel KM. MicroRNA-mediated regulation of T helper cell differentiation and plasticity., 2013, 13(9): 666–678.

[63] Chen C, Zhou YF, Wang JQ, Yan YP, Peng LS, Qiu W. Dysregulated microRNA involvement in multiple sclerosis by induction of T helper 17 cell differentiation., 2018, 9: 1256.

[64] Ichiyama K, Gonzalez-Martin A, Kim BS, Jin HY, Jin W, Xu W, Sabouri-Ghomi M, Xu SB, Zheng P, Xiao CC, Dong C. The microRNA-183-96-182 cluster promotes T helper 17 cell pathogenicity by negatively regulating transcription factor Foxo1 expression., 2016, 44(6): 1284–1298.

[65] Bamodu OA, Huang WC, Lee WH, Wu A, Wang LS, Hsiao M, Yeh CT, Chao TY. Aberrant KDM5B expression promotes aggressive breast cancer through MALAT1 overexpression and downregulation of hsa-miR-448., 2016, 16: 160.

[66] Hong XH, Xu Y, Qiu XF, Zhu YK, Feng X, Ding ZJ, Zhang SF, Zhong LF, Zhuang YF, Su C, Hong XY, Cai JC. MiR-448 promotes glycolytic metabolism of gastric cancer by downregulating KDM2B., 2016, 7(16): 22092–22102.

[67] Lou Q, Liu RX, Yang XL, Li WQ, Huang LL, Wei LL, Tan HL, Xiang NL, Chan K, Chen JX, Liu HL. MiR-448 targets IDO1 and regulates CD8+T cell response in human colon cancer., 2019, 7(1): 210.

[68] Sasahira T, Kurihara M, Nishiguchi Y, Fujiwara R, Kirita T, Kuniyasu H. NEDD 4 binding protein 2-like 1 promotes cancer cell invasion in oral squamous cell carcinoma., 2016, 469(2): 163–172.

[69] Wu RH, He QY, Chen HT, Xu M, Zhao N, Xiao Y, Tu QQ, Zhang WJ, Bi XY. MicroRNA-448 promotes multiple sclerosis development through induction of Th17 response through targeting protein tyrosine phosphatase non-receptor type 2 (PTPN2)., 2017, 486(3): 759–766.

[70] Keller A, Leidinger P, Lange J, Borries A, Schroers H, Scheffler M, Lenhof HP, Ruprecht K, Meese E. Multiple sclerosis: microRNA expression profiles accurately differentiate patients with relapsing-remitting disease from healthy controls., 2009, 4(10): e7440.

[71] Zhu ED, Wang X, Zheng B, Wang Q, Hao JL, Chen SM, Zhao Q, Zhao LQ, Wu ZZ, Yin ZN. MiR-20b suppresses Th17 differentiation and the pathogenesis of experimental autoimmune encephalomyelitis by targeting RORγt and STAT3., 2014, 192(12): 5599–5609.

[72] Chen J, Martindale JL, Abdelmohsen K, Kumar G, Fortina PM, Gorospe M, Rostami A, Yu SG. RNA-binding protein HuR promotes Th17 cell differentiation and can be targeted to reduce autoimmune neuroinflammation., 2020, 204(8): 2076–2087.

[73] Chen J, Martindale JL, Cramer C, Gorospe M, Atasoy U, Drew PD, Yu SG. The RNA-binding protein HuR contributes to neuroinflammation by promoting C-C chemokine receptor 6 (CCR6) expression on Th17 cells., 2017, 292(35): 14532–14543.

[74] Roy DG, Chen J, Mamane V, Ma EH, Muhire BM, Sheldon RD, Shorstova T, Koning R, Johnson RM, Esaulova E, Williams KS, Hayes S, Steadman M, Samborska B, Swain A, Daigneault A, Chubukov V, Roddy TP, Foulkes W, Pospisilik JA, Bourgeois-Daigneault MC, Artyomov MN, Witcher M, Krawczyk CM, Larochelle C, Jones RG. Methionine metabolism shapes T helper cell responses through regulation of epigenetic reprogramming., 2020, 31(2): 250–266.e9.

[75] Cho JJ, Xu ZW, Parthasarathy U, Drashansky TT, Helm EY, Zuniga AN, Lorentsen KJ, Mansouri S, Cho JY, Edelmann MJ, Duong DM, Gehring T, Seeholzer T, Krappmann D, Uddin MN, Califano D, Wang RL, Jin L, Li HM, Lv DW, Zhou DH, Zhou L, Avram D. Hectd3 promotes pathogenic Th17 lineage through Stat3 activation and Malt1 signaling in neuroinflammation., 2019, 10(1): 701.

[76] Perfetto SP, Chattopadhyay PK, Roederer M. Seventeen- colour flow cytometry: unravelling the immune system., 2004, 4(8): 648–655.

[77] Shalek AK, Satija R, Adiconis X, Gertner RS, Gaublomme JT, Raychowdhury R, Schwartz S, Yosef N, Malboeuf C, Lu D, Trombetta JJ, Gennert D, Gnirke A, Goren A, Hacohen N, Levin JZ, Park H, Regev A. Single-cell trans-criptomics reveals bimodality in expression and splicing in immune cells., 2013, 498(7453): 236–240.

[78] Gaublomme JT, Yosef N, Lee Y, Gertner RS, Yang LV, Wu C, Pandolfi PP, Mak T, Satija R, Shalek AK, Kuchroo VK, Park H, Regev A. Single-cell genomics unveils critical regulators of Th17 cell pathogenicity., 2015, 163(6): 1400–1412.

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(jí)重點(diǎn)研發(fā)計(jì)劃(社會(huì)發(fā)展)項(xiàng)目(編號(hào)：SBE2021741263)和南京醫(yī)科大學(xué)第二附屬醫(yī)院789人才培養(yǎng)計(jì)劃(編號(hào)：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(zhuān)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(hù)。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)