雙面守護者：解碼Toll樣受體在免疫與疾病中的關鍵角色

1. Toll樣受體家族簡介

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

1.1 TLR家族結(jié)構(gòu)

TLR是I型跨膜蛋白，含有配體識別富含亮氨酸重復序列（LRR）結(jié)構(gòu)域、跨膜結(jié)構(gòu)域和Toll/白細胞介素1受體（TIR）同源結(jié)構(gòu)域。LRR結(jié)構(gòu)域負責配體識別，而細胞質(zhì)TIR結(jié)構(gòu)域通過與其銜接蛋白相互作用來啟動下游信號級聯(lián)反應。迄今為止，已在人類中鑒定出10個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TLR在功能上分為兩個亞組。一組由TLR1、TLR2、TLR4、TLR5、TLR6和TLR10組成，它們定位于細胞膜，主要識別脂質(zhì)、脂蛋白和蛋白質(zhì)等細菌成分。另一組由TLR3、TLR7、TLR8和TLR9組成，它們定位于內(nèi)體/溶酶體，主要識別微生物核酸。TLR在多種造血細胞和非造血細胞中表達，包括效應免疫細胞（如樹突狀細胞、巨噬細胞、淋巴細胞、粒細胞）、造血干細胞和祖細胞以及非免疫細胞。

1.3 TLR信號傳導途徑

TLR的信號傳導涉及細胞內(nèi)銜接蛋白的募集，最終導致轉(zhuǎn)錄因子的激活以及促炎細胞因子的產(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隨后被招募到該復合物中，刺激TAK1，隨后激活NF-κB和MAPK通路，并產(chǎn)生促炎細胞因子。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信號。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依賴性途徑傳導信號

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

2. TLR信號傳導與癌癥的相關研究

通過TLRs對免疫系統(tǒng)的外源性激活一方面可能是一種抗癌策略，但另一方面會加劇潛在的慢性炎癥，這反過來又會進一步有利于癌癥的進展。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可降低腫瘤負荷、減少血管生成和腫瘤細胞增殖，并伴有腫瘤細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，與區(qū)域淋巴結(jié)受累和PCa侵襲性相關^[4]。TLR4與PCa細胞系、肝細胞癌（HCC）增殖和侵襲能力以及低生存率相關，是革蘭氏陰性肺炎增強的非小細胞肺癌（NSCLC）轉(zhuǎn)移的可行治療靶點^[5-7]。阿霉素誘導的HMGB1釋放會激活乳腺癌細胞中的TLR2信號傳導，從而導致化療耐藥表型^[8]。與此相反，TLR2通過激活細胞內(nèi)在細胞周期停滯途徑和促炎衰老相關分泌表型來抑制肺癌的早期進展^[9]。TLR介導的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信號傳導可改善促炎細胞因子的產(chǎn)生并減少二乙基亞硝胺誘導的肝癌發(fā)生^[11]。這些研究突出了TLR信號傳導在癌癥治療中的潛在價值。

圖3 TLR2依賴性化療耐藥機制的示意圖

（圖片源于《Oncoimmunology》^[8]）

3. TLR信號傳導與心血管疾病的相關研究

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

圖4 ANG II對高血壓和心臟肥大的差異效應模型示意圖

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

4. TLR信號傳導與肺部疾病的相關研究

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

5. TLR信號傳導與炎癥性腸病的相關研究

TLR作為腸道微生物群的傳感器，在維持腸道穩(wěn)態(tài)、控制免疫反應和塑造微生物群方面發(fā)揮著關鍵作用。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）之間存在關聯(lián)^[36,37]。ERS和TLR2在炎癥性腸病（IBD）中上調(diào)，ERS可能促進TLR2通路介導的炎癥反應^[38]。抑制TLR2/NF-κB信號通路的激活可有效預防葡聚糖硫酸鈉（DSS）誘導的IBD^[39]。TLR3介導CCL20、CXCL10在結(jié)腸上皮細胞中的表達，參與IBD中的活動性炎癥^[40,41]。抑制TLR4/NF-κB/HIF-1α軸來增強UC治療結(jié)局，從而減輕炎癥反應，改善結(jié)腸病變^[42,43]。激活TLR4/NF-κB通路加重DSS誘導的IBD的炎癥和焦亡^[44]。TLR6是腸道相關淋巴組織中Th1和Th17反應的重要驅(qū)動因素^[45]。與前面這些研究相反，TLR3和TLR7識別駐留病毒介導的干擾素β產(chǎn)生改善腸道炎癥^[46]，激活TLR9信號通路改善活動性UC患者的臨床癥狀^[47]。這些發(fā)現(xiàn)為靶向TLR信號傳導治療IBD提供幫助。

圖5 TLR4/NF-κB/HIF-1α通路促進UC炎癥的分子機制

（圖片源于《Drug Des Devel Ther》^[42]）

6. TLR信號傳導與神經(jīng)退行性疾病的相關研究

TLR的激活能夠誘導對中樞神經(jīng)系統(tǒng)損傷或感染的免疫和炎癥反應。靶向抑制TLR2、TLR4通路介導的神經(jīng)炎癥改善帕金森病的運動和認知障礙^[48,49]。抑制TLR4/NF-κB信號通路可以通過抑制神經(jīng)炎癥和細胞凋亡來改善Aβ誘導的記憶功能障礙^[50]。神經(jīng)膠質(zhì)細胞中TLR4信號傳導增強促進肌萎縮側(cè)索硬化癥（ALS）小鼠的疾病進展^[51]。microRNA和ssRNA可以充當信號分子，激活中樞神經(jīng)系統(tǒng)中的TLR7信號傳導，促進神經(jīng)變性和神經(jīng)炎癥^[52,53]。TLR9信號傳導的激活會通過誘導氧化應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，認知能力下降會顯著加速^[55]。因此，TLR可以作為開發(fā)神經(jīng)保護藥物的潛在藥物病理學靶點。

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