新一期出版的國際學(xué)術(shù)期刊《自然—免疫學(xué)》雜志發(fā)表了中國工程院院士,、醫(yī)學(xué)免疫學(xué)國家重點(diǎn)實(shí)驗(yàn)室主任,、第二軍醫(yī)大學(xué)免疫學(xué)研究所所長曹雪濤研究小組在免疫識(shí)別與免疫調(diào)控研究領(lǐng)域的成果,。該研究小組發(fā)現(xiàn),，免疫細(xì)胞膜表面整合素CD11b能夠通過一系列信號(hào)轉(zhuǎn)導(dǎo)機(jī)制促進(jìn)天然免疫分子的泛素化蛋白降解,，從而負(fù)向調(diào)節(jié)天然免疫應(yīng)答中免疫細(xì)胞產(chǎn)生炎癥性細(xì)胞因子與干擾素,，反饋抑制了免疫反應(yīng)與炎癥發(fā)生,，避免病原體感染過程中免疫應(yīng)答與炎癥反應(yīng)過度發(fā)生造成機(jī)體組織的損害,，從而維持機(jī)體內(nèi)環(huán)境穩(wěn)定與健康。
同期《自然—免疫學(xué)》為此論文配發(fā)了由哈佛大學(xué)教授Luster撰寫的專題評(píng)論,。評(píng)論認(rèn)為該研究為人們深入認(rèn)識(shí)機(jī)體如何適度控制病原體入侵之后所誘發(fā)的炎癥反應(yīng)的發(fā)生發(fā)展提出了新的機(jī)制,，為天然免疫與炎癥反應(yīng)的負(fù)向調(diào)控機(jī)制深入研究打開了新的窗口，提出的靶向抑制整合素CD11b及其觸發(fā)的信號(hào)通路將為防治自身免疫性疾病和炎癥性疾病的藥物設(shè)計(jì)提供新的思路,。這是繼兩個(gè)月前該雜志發(fā)表曹雪濤等發(fā)現(xiàn)免疫細(xì)胞感知病原物入侵并啟動(dòng)免疫反應(yīng)的新分子機(jī)制研究結(jié)果后,，再次刊登該研究小組的論文。
病毒,、細(xì)菌等致病性病原微生物一旦入侵機(jī)體,，將迅速啟動(dòng)機(jī)體天然免疫應(yīng)答反應(yīng)并觸發(fā)炎癥性反應(yīng)。令免疫學(xué)家感興趣的是,，機(jī)體免疫系統(tǒng)如何在有效啟動(dòng)天然免疫應(yīng)答效應(yīng)以清除病原微生物的同時(shí),，又通過何種分子機(jī)制避免炎癥性反應(yīng)的過度發(fā)生以減輕病原微生物入侵對(duì)機(jī)體組織的損害？
在國家自然科學(xué)基金和“973”項(xiàng)目的資助下,，曹雪濤與韓超峰博士等發(fā)現(xiàn),，整合素CD11b基因缺失小鼠一旦感染細(xì)菌，將產(chǎn)生大量的炎癥性細(xì)胞因子與干擾素而易于死亡,；進(jìn)一步研究表明,，病原體感染可以激活巨噬細(xì)胞、樹突狀細(xì)胞等免疫細(xì)胞表面的CD11b分子,，然后CD11b分子向免疫細(xì)胞內(nèi)觸發(fā)了一系列信號(hào)轉(zhuǎn)導(dǎo),，導(dǎo)致兩個(gè)重要的天然免疫分子MyD88和TRIF的磷酸化，并促進(jìn)了E3泛素化連接酶對(duì)這兩種磷酸化免疫分子的蛋白降解,，從而抑制了免疫細(xì)胞炎癥性信號(hào)通路的發(fā)生并適度控制了炎癥性細(xì)胞因子的產(chǎn)生,，由此，整合素CD11b分子能通過介導(dǎo)不同信號(hào)轉(zhuǎn)導(dǎo)通路的交叉調(diào)控而參與免疫應(yīng)答與炎癥發(fā)生的反饋抑制,。該結(jié)果提示,，整合素CD11b分子的異常可能與炎癥性疾病的發(fā)生發(fā)展有關(guān),，進(jìn)一步尋找選擇性地激活整合素CD11b分子的藥物將有可能利于炎癥性自身免疫性疾病等的預(yù)防與治療,。(生物谷Bioon.com)
生物谷推薦原文出處：
Nature Immunology doi:10.1038/ni.1908
Integrin CD11b negatively regulates TLR-triggered inflammatory responses by activating Syk and promoting degradation of MyD88 and TRIF via Cbl-b
Chaofeng Han,Jing Jin,Sheng Xu,Haibo Liu,Nan Li& Xuetao Cao
Integrins are critical for the migration and function of leukocytes in inflammation. However, the interaction between integrin αM (CD11b), which has high expression in monocytes and macrophages, and Toll-like receptor (TLR)-triggered innate immunity remains unclear. Here we report that CD11b deficiency enhanced TLR-mediated responses in macrophages, rendering mice more susceptible to endotoxin shock and Escherichia coli–caused sepsis. CD11b was activated by TLR-triggered phosphatidylinositol 3-OH kinase (PI(3)K) and the effector RapL and fed back to inhibit TLR signaling by activating the tyrosine kinases Src and Syk. Syk interacted with and induced tyrosine phosphorylation of MyD88 and TRIF, which led to degradation of these adaptor molecules by the E3 ubiquitin ligase Cbl-b. Thus, TLR-triggered, active CD11b integrin engages in crosstalk with the MyD88 and TRIF pathways and subsequently inhibits TLR signaling in innate immune responses.
