中性粒細胞胞外陷阱
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中性粒細胞胞外誘捕器(NET)是胞外纖維網絡,主要由中性粒細胞的DNA組成,與病原體結合。[2]中性粒細胞是免疫系統抵禦感染的第一道防線,通常被認為通過兩種策略殺死入侵的病原體:吞噬微生物和分泌抗微生物劑。 在2004年,它被確定了新的第三個功能:生產及形成NET。NET允許中性粒細胞殺死細胞外病原體,同時最大限度地減少對宿主細胞的損害。[3]在體外用藥物佛波醇肉豆蔻酸酯(PMA)、白細胞介素-8(IL-8)或脂多糖(LPS)激活後,中性粒細胞會通過活性過程釋放顆粒蛋白和染色質以形成稱為NET的細胞外原纖維基質。 [2]
![](http://upload.wikimedia.org/wikipedia/commons/thumb/5/50/Neutrophil_Extracellular_Traps.png/250px-Neutrophil_Extracellular_Traps.png)
結構和組成
編輯高解像度掃描電子顯微鏡顯示NET由DNA和球狀蛋白質結構域組成,直徑分別為15至17納米和25納米。這些將會聚集成直徑為50納米的較大螺紋。[2]然而,在流動條件下,NET可以形成更大的結構,長度和寬度達到數百納米。 [4]
免疫熒光分析證實NET含有來自嗜天青顆粒(中性粒細胞彈性蛋白酶、組織蛋白酶G和髓過氧化物酶)、特定顆粒(乳鐵蛋白)、三級顆粒(明膠酶)和細胞質的蛋白質;然而,NET中不存在CD63 、肌動蛋白、微管蛋白和各種其他細胞質蛋白。[2][5]
抗微生物活性
編輯NET使用對DNA較為高親和的抗菌蛋白(如中性粒細胞彈性蛋白酶、組織蛋白酶G和組蛋白)解除病原體的武裝。 [6] NET提供高濃度的抗微生物成分,並在細胞外結合、解除和殺死微生物,而與吞噬細胞的攝取無關。除了它們的抗菌特性外,NET還可以作為防止病原體進一步傳播的物理屏障。此外,將顆粒蛋白輸送到 NET中可以阻止蛋白酶等潛在的有害蛋白擴散並在炎症部位附近的組織中引起損傷。NET的形成也被證明可以增強巨噬細胞對多種細菌病原體的殺菌活性。[7][8]
最近研究表明,不僅是細菌,致病性的真菌(如白色念珠菌)也會誘導中性粒細胞形成 NET,捕獲並殺死白色念珠菌的菌絲和酵母形式的細胞。 [9] NET也被證明與兒童惡性瘧原蟲感染有關。[10]
雖然最初提出NET會在細菌或酵母菌感染部位的組織中形成,但NET也被證明會在敗血症期間在血管內形成(特別是在肺部的毛細血管和肝竇)。血管內NET的形成受到嚴格控制並受血小板調節,血小板通過血小板TLR4感知嚴重感染,然後結合併激活中性粒細胞形成 NET。血小板誘導的NET形成非常迅速(在幾分鐘內),可能會或不會導致中性粒細胞死亡。[11]在血管中形成的NET可以在循環細菌通過血管時捕獲它們。在流動下細菌的捕獲已在體外流室中直接成像,活體顯微鏡顯示細菌捕獲發生在肝竇和肺毛細血管(血小板與中性粒細胞結合的部位)中。[4]
NETosis
編輯NET的激活和釋放,或NETosis,是一個動態過程,可以有兩種形式:自殺和重要NETosis(vital NETosis)。總體而言,這兩種NETosis過程的許多關鍵組成部分是相似的,但是在刺激、時間和最終結果方面存在關鍵差異。[12]
激活途徑
編輯完整的NETosis激活途徑仍在研究中,但一些關鍵蛋白質已被確定,並且該途徑的全貌正在逐漸顯現。該過程被認為始於,通過活性氧類為中介,激活蛋白質-精氨酸脫亞胺酶4(PADI4)的NADPH氧化酶。 PAD4負責中性粒細胞中組蛋白的瓜氨酸化,導致染色質去濃縮化。[12]還有一種不依賴NADPH氧化酶的NETosis形式,僅依賴於線粒體衍生的活性氧類。[13]隨後,髓氧化物酶(MPO)和中性粒細胞彈性蛋白酶(NE)為代表的嗜天青顆粒將會進入細胞核並進行進一步的去冷凝過程,最終導致核膜破裂。未濃縮的染色質進入細胞質,其中額外的顆粒和細胞質蛋白被添加到早期NET中。該過程的結果取決於激活的NETosis途徑。[12]
自殺性NETosis
編輯2007年的一項研究首次描述了自殺性NETosis。該研究指出,NET的釋放導致中性粒細胞死亡的途徑與細胞凋亡或壞死不同。[14]在自殺性NETosis中,細胞內NET形成之後是細胞膜破裂,將其釋放到細胞外空間。這種NETosis途徑可以通過激活toll樣受體 (TLR)、Fc受體和具有各種配體(如抗體、PMA等)的補體受體來啟動。[12][15]目前的理解是,在這些受體激活後,下游信號傳導導致鈣從內質網釋放。鈣的這種細胞內流入反過來激活NADPH氧化酶,導致如上所述的NETosis途徑的激活。[15]值得注意的是,即使有高水平的PMA刺激,自殺性NETosis也可能需要數小時,而vital NETosis可以在幾分鐘內完成。[12]
重要NETosis(vital NETosis)
編輯Vital NETosis可由細菌性脂多糖(LPS)、其他「細菌產物、TLR4激活的血小板或與TLR2配體串聯的補體蛋白」刺激。[12]通過細胞核的起泡,vital NETosis成為了可能,從而產生一個充滿DNA的囊泡,該囊泡被胞吐並保持質膜完整。[12]它的快速形成和釋放不會導致中性粒細胞死亡。已經注意到,中性粒細胞可以在vital NETosis後繼續吞噬和殺死微生物,突出了中性粒細胞的抗微生物多功能性。[15]
調節
編輯NET的形成受脂氧合酶途徑的調節——在某些形式的激活(包括與細菌接觸)期間,花生四烯酸5-脂氧合酶形成抑制NET形成的5-HETE-磷脂。[16]實驗室的實驗證據表明,NET被巨噬細胞吞噬並降解。[17]
NET相關的宿主傷害
編輯NET也可能對宿主產生有害影響,因為組蛋白複合物的細胞外暴露可能在系統性紅斑狼瘡等自身免疫性疾病的發展過程中發揮作用。[18]NET也可能在炎症性疾病中發揮作用,因為NET可以在子癇前症中發現,這是一種與妊娠相關的炎症性疾病,已知中性粒細胞被激活。[19]在炎症性腸病和潰瘍性結腸炎患者的結腸黏膜中也有NET的報告。[20]NET還與感染惡性瘧原蟲瘧疾的兒童產生IgG抗核雙鏈DNA抗體有關。[10]在癌症患者中也發現了NET。[21]臨床前研究表明,NET共同負責與癌症相關的病理,如血栓形成、器官衰竭和轉移形成。[22]
NET已被證明有助於HIV/SIV的發病機制。 NET能夠捕獲HIV病毒粒子並摧毀它們。[23]抗病毒藥物可以在HIV/SIV的整個病程中,減少NET產生及增加。此外,NET能夠捕獲和殺死各種免疫細胞群,例如CD4+和 CD8+T 細胞、B細胞和單核細胞。這種效應不僅見於血液中的中性粒細胞,也見於各種組織,如腸道、肺、肝臟和血管。 NET可能通過捕獲血小板和表達組織因子導致HIV的高凝狀態。[24]
NET在血栓形成中扮演重要角色,並且與中風有關。[25][26][27]
這些觀察結果表明,NET可能在感染性、炎症性和血栓性疾病的發病機制中發揮重要作用。[28][29][30]
由於NET的帶電和「粘性」性質,它們可能會通過增加痰液粘度而成為囊性纖維化患者的困擾。治療的重點是分解痰中的DNA,痰中主要由宿主NET DNA組成。
發表在美國醫學會心臟病學雜誌(JAMA Cardiology)上的一項小型研究表明,NET 在發生ST 段抬高心肌梗塞的COVID-19患者中發揮了重要作用。[31]
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