雙面守護(hù)者：解碼Toll樣受體在免疫與疾病中的關(guān)鍵角色

1. Toll樣受體家族簡(jiǎn)介

Toll樣受體（TLR）是一組模式識(shí)別受體，在免疫系統(tǒng)的發(fā)育和維持中發(fā)揮著重要作用。這些受體可識(shí)別外來病原體相關(guān)分子模式（PAMP），以及細(xì)胞損傷的內(nèi)源性副產(chǎn)物，即損傷相關(guān)分子模式（DAMP），通過TLR的信號(hào)傳導(dǎo)導(dǎo)致促炎細(xì)胞因子和其他炎癥反應(yīng)介質(zhì)的產(chǎn)生。因此，TLR及其信號(hào)通路對(duì)于先天免疫系統(tǒng)和適應(yīng)性免疫系統(tǒng)的功能都至關(guān)重要。

1.1 TLR家族結(jié)構(gòu)

TLR是I型跨膜蛋白，含有配體識(shí)別富含亮氨酸重復(fù)序列（LRR）結(jié)構(gòu)域、跨膜結(jié)構(gòu)域和Toll/白細(xì)胞介素1受體（TIR）同源結(jié)構(gòu)域。LRR結(jié)構(gòu)域負(fù)責(zé)配體識(shí)別，而細(xì)胞質(zhì)TIR結(jié)構(gòu)域通過與其銜接蛋白相互作用來啟動(dòng)下游信號(hào)級(jí)聯(lián)反應(yīng)。迄今為止，已在人類中鑒定出10個(gè)TLR（TLR1-10）。大多數(shù)TLR激活后以同源二聚體行使功能，但TLR2除外，TLR2與TLR1或TLR6以異二聚體形式行使功能。

圖1 TLR的結(jié)構(gòu)域示意圖

（圖片源于《Protein Sci》^[1]）

1.2 TLR家族分布

人類中的10個(gè)TLR在功能上分為兩個(gè)亞組。一組由TLR1、TLR2、TLR4、TLR5、TLR6和TLR10組成，它們定位于細(xì)胞膜，主要識(shí)別脂質(zhì)、脂蛋白和蛋白質(zhì)等細(xì)菌成分。另一組由TLR3、TLR7、TLR8和TLR9組成，它們定位于內(nèi)體/溶酶體，主要識(shí)別微生物核酸。TLR在多種造血細(xì)胞和非造血細(xì)胞中表達(dá)，包括效應(yīng)免疫細(xì)胞（如樹突狀細(xì)胞、巨噬細(xì)胞、淋巴細(xì)胞、粒細(xì)胞）、造血干細(xì)胞和祖細(xì)胞以及非免疫細(xì)胞。

1.3 TLR信號(hào)傳導(dǎo)途徑

TLR的信號(hào)傳導(dǎo)涉及細(xì)胞內(nèi)銜接蛋白的募集，最終導(dǎo)致轉(zhuǎn)錄因子的激活以及促炎細(xì)胞因子的產(chǎn)生。除TLR3外，大多數(shù)活化的TLR招募MyD88和IRAK家族的成員（包括IRAK1、IRAK2和IRAK4）。這些蛋白質(zhì)共同形成“Myddosome”。TRAF6隨后被招募到該復(fù)合物中，刺激TAK1，隨后激活NF-κB和MAPK通路，并產(chǎn)生促炎細(xì)胞因子。TLR3募集TRIF而不是MyD88，TLR4通過MyD88依賴性和TRIF依賴性兩條途徑傳導(dǎo)信號(hào)。TRIF與TRAF3結(jié)合，然后招募TBK1和IKKε，從而激活IRF3并刺激I型干擾素的產(chǎn)生。此外，TRIF與TRAF6相互作用，促進(jìn)NF-κB和MAPK通路的激活。

圖2 TLR通過MyD88依賴性或TRIF依賴性途徑傳導(dǎo)信號(hào)

（圖片源于《Cold Spring Harb Perspect Biol》^[2]）

2. TLR信號(hào)傳導(dǎo)與癌癥的相關(guān)研究

通過TLRs對(duì)免疫系統(tǒng)的外源性激活一方面可能是一種抗癌策略，但另一方面會(huì)加劇潛在的慢性炎癥，這反過來又會(huì)進(jìn)一步有利于癌癥的進(jìn)展。在慢性阻塞性肺疾?。?/span>COPD）背景下的K-ras突變小鼠中，敲除TLR2、TLR4或TLR9可降低腫瘤負(fù)荷、減少血管生成和腫瘤細(xì)胞增殖，并伴有腫瘤細(xì)胞凋亡增加和腫瘤微環(huán)境重新編程為抗腫瘤環(huán)境^[3]。TLR9在前列腺癌（PCa）中高表達(dá)，與區(qū)域淋巴結(jié)受累和PCa侵襲性相關(guān)^[4]。TLR4與PCa細(xì)胞系、肝細(xì)胞癌（HCC）增殖和侵襲能力以及低生存率相關(guān)，是革蘭氏陰性肺炎增強(qiáng)的非小細(xì)胞肺癌（NSCLC）轉(zhuǎn)移的可行治療靶點(diǎn)^[5-7]。阿霉素誘導(dǎo)的HMGB1釋放會(huì)激活乳腺癌細(xì)胞中的TLR2信號(hào)傳導(dǎo)，從而導(dǎo)致化療耐藥表型^[8]。與此相反，TLR2通過激活細(xì)胞內(nèi)在細(xì)胞周期停滯途徑和促炎衰老相關(guān)分泌表型來抑制肺癌的早期進(jìn)展^[9]。TLR介導(dǎo)的PI3K激活通過產(chǎn)生半乳糖凝集素1調(diào)節(jié)卵巢癌的侵襲和轉(zhuǎn)移^[10]。抑制TLR信號(hào)傳導(dǎo)可改善促炎細(xì)胞因子的產(chǎn)生并減少二乙基亞硝胺誘導(dǎo)的肝癌發(fā)生^[11]。這些研究突出了TLR信號(hào)傳導(dǎo)在癌癥治療中的潛在價(jià)值。

圖3 TLR2依賴性化療耐藥機(jī)制的示意圖

（圖片源于《Oncoimmunology》^[8]）

3. TLR信號(hào)傳導(dǎo)與心血管疾病的相關(guān)研究

TLR的激活在心血管疾病的發(fā)展、進(jìn)展和結(jié)果中起著重要作用。TLR1、TLR2、TLR5、TLR6和TLR7通過增強(qiáng)巨噬細(xì)胞積累和T細(xì)胞反應(yīng)性，調(diào)節(jié)病變和全身炎癥促進(jìn)動(dòng)脈粥樣硬化進(jìn)展^[12-15]。TLR2信號(hào)傳導(dǎo)對(duì)于保護(hù)心臟免受小鼠衰老相關(guān)的不良重塑和收縮功能障礙至關(guān)重要^[16]。ANG II誘導(dǎo)的高血壓和心臟肥大與TLR4和TLR3的差異激活有關(guān)^[17,18]。TLR9是高血壓中血管周圍脂肪組織功能障礙的關(guān)鍵介質(zhì)，導(dǎo)致炎癥、氧化應(yīng)激和血管損傷^[19]。研究顯示TLR3是主動(dòng)脈瓣鈣化保守途徑中的關(guān)鍵元素^[20]。TLR4和MyD88之間的新型SNP相互作用與冠狀動(dòng)脈疾病風(fēng)險(xiǎn)增加相關(guān)^[21]。TLR6通過氧化應(yīng)激和炎癥反應(yīng)促進(jìn)了心肌纖維化的進(jìn)展^[22]。這些研究表明更好地了解心血管疾病中TLR信號(hào)傳導(dǎo)可能有助于開發(fā)靶向TLR的新療法。

圖4 ANG II對(duì)高血壓和心臟肥大的差異效應(yīng)模型示意圖

（圖片源于《Am J Physiol Heart Circ Physiol》^[17]）

4. TLR信號(hào)傳導(dǎo)與肺部疾病的相關(guān)研究

由于肺部暴露于多種傳染源、抗原和宿主來源的危險(xiǎn)信號(hào)，肺部的基質(zhì)細(xì)胞和髓系細(xì)胞表達(dá)TLR聚集體，這些TLR可以感知DAMP以及PAMP并觸發(fā)涉及宿主防御的TLR相關(guān)信號(hào)傳導(dǎo)。TLR1和TLR10基因的變異增加了毛細(xì)支氣管炎后哮喘的風(fēng)險(xiǎn)^[23]，TLR7和TLR8可能賦予對(duì)哮喘的易感性^[24]。TLR2和TLR4中的SNP與慢性阻塞性肺?。?/span>COPD）的嚴(yán)重程度和疾病進(jìn)展相關(guān)^[25]，TLR7通過肥大細(xì)胞活性介導(dǎo)肺氣腫和COPD^[26]。抑制TLR2、TLR6、TLR3、TLR4介導(dǎo)的NF-κB和MAPK通路減輕肺炎支原體、LPS、抗體介導(dǎo)的輸血相關(guān)的肺損傷和二氧化硅誘導(dǎo)的肺纖維化^[27-32]。TLR4表達(dá)誘導(dǎo)炎癥的持續(xù)激活，巨噬細(xì)胞病理性轉(zhuǎn)移，是COVID-19致死的機(jī)制之一^[33]。TLR5的抑制消除了囊性纖維化氣道細(xì)胞在暴露于銅綠假單胞菌后產(chǎn)生的破壞性炎癥反應(yīng)^[34]。肺挫傷后的損傷細(xì)胞通過TLR9激活急性炎癥反應(yīng)^[35]。因此抑制TLR可能是肺損傷的新治療策略。

5. TLR信號(hào)傳導(dǎo)與炎癥性腸病的相關(guān)研究

TLR作為腸道微生物群的傳感器，在維持腸道穩(wěn)態(tài)、控制免疫反應(yīng)和塑造微生物群方面發(fā)揮著關(guān)鍵作用。TLR1、TLR2、TLR5和TLR6基因中的非同義變異與克羅恩?。?/span>CD）和潰瘍性結(jié)腸炎（UC）之間存在關(guān)聯(lián)^[36,37]。ERS和TLR2在炎癥性腸病（IBD）中上調(diào)，ERS可能促進(jìn)TLR2通路介導(dǎo)的炎癥反應(yīng)^[38]。抑制TLR2/NF-κB信號(hào)通路的激活可有效預(yù)防葡聚糖硫酸鈉（DSS）誘導(dǎo)的IBD^[39]。TLR3介導(dǎo)CCL20、CXCL10在結(jié)腸上皮細(xì)胞中的表達(dá)，參與IBD中的活動(dòng)性炎癥^[40,41]。抑制TLR4/NF-κB/HIF-1α軸來增強(qiáng)UC治療結(jié)局，從而減輕炎癥反應(yīng)，改善結(jié)腸病變^[42,43]。激活TLR4/NF-κB通路加重DSS誘導(dǎo)的IBD的炎癥和焦亡^[44]。TLR6是腸道相關(guān)淋巴組織中Th1和Th17反應(yīng)的重要驅(qū)動(dòng)因素^[45]。與前面這些研究相反，TLR3和TLR7識(shí)別駐留病毒介導(dǎo)的干擾素β產(chǎn)生改善腸道炎癥^[46]，激活TLR9信號(hào)通路改善活動(dòng)性UC患者的臨床癥狀^[47]。這些發(fā)現(xiàn)為靶向TLR信號(hào)傳導(dǎo)治療IBD提供幫助。

圖5 TLR4/NF-κB/HIF-1α通路促進(jìn)UC炎癥的分子機(jī)制

（圖片源于《Drug Des Devel Ther》^[42]）

6. TLR信號(hào)傳導(dǎo)與神經(jīng)退行性疾病的相關(guān)研究

TLR的激活能夠誘導(dǎo)對(duì)中樞神經(jīng)系統(tǒng)損傷或感染的免疫和炎癥反應(yīng)。靶向抑制TLR2、TLR4通路介導(dǎo)的神經(jīng)炎癥改善帕金森病的運(yùn)動(dòng)和認(rèn)知障礙^[48,49]。抑制TLR4/NF-κB信號(hào)通路可以通過抑制神經(jīng)炎癥和細(xì)胞凋亡來改善Aβ誘導(dǎo)的記憶功能障礙^[50]。神經(jīng)膠質(zhì)細(xì)胞中TLR4信號(hào)傳導(dǎo)增強(qiáng)促進(jìn)肌萎縮側(cè)索硬化癥（ALS）小鼠的疾病進(jìn)展^[51]。microRNA和ssRNA可以充當(dāng)信號(hào)分子，激活中樞神經(jīng)系統(tǒng)中的TLR7信號(hào)傳導(dǎo)，促進(jìn)神經(jīng)變性和神經(jīng)炎癥^[52,53]。TLR9信號(hào)傳導(dǎo)的激活會(huì)通過誘導(dǎo)氧化應(yīng)激和炎癥來加劇神經(jīng)退行性變^[54]。相反，另有研究表明TLR2作為骨髓來源免疫細(xì)胞的內(nèi)源性受體有助于清除有毒Aβ；在TLR2缺乏的情況下，認(rèn)知能力下降會(huì)顯著加速^[55]。因此，TLR可以作為開發(fā)神經(jīng)保護(hù)藥物的潛在藥物病理學(xué)靶點(diǎn)。

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