Duan Zilei, Fang Yaqun, Sun Yang, Luan Ning, Chen Xue, Chen Mengrou, Han Yajun, Yin Yizhu, Mwangi James, Niu Junkun, Wang Kunhua, Miao Yinglei, Zhang Zhiye, Lai Ren
Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences/Key Laboratory of Bioactive Peptides of Yunnan Province, Kunming Institute of Zoology, Kunming 650223, China.
Life Sciences College of Nanjing Agricultural University, Nanjing 210095, China.
Sci Bull (Beijing). 2018 Oct 30;63(20):1364-1375. doi: 10.1016/j.scib.2018.09.014. Epub 2018 Sep 22.
Bacterial DNA (bacDNA) is frequently found in serum of patient with ulcerative colitis (UC) and Crohn's disease, even blood bacterial culture is negative. How bacDNA evades immune elimination and is translocated into blood remain unclear. Here, we showed that bacDNA avoids elimination and disables bacteria-killing function of antimicrobial peptide LL-37 (Cramp in mice) by forming complex with LL-37, which is inducible after culture with bacteria or bacterial products. Elevated LL-37-bacDNA complex was found in plasma and lesions of patients with UC. LL-37-bacDNA promoted inflammation by inducing Th1, Th2 and Th17 differentiation and activating toll-like receptor-9 (TLR9). The complex also increased paracellular permeability, which possibly combines its inflammatory effects to promote local damage and bacDNA translocation into blood. Cramp-bacDNA aggravated mouse colitis severity while interference with the complex ameliorated the disease. The study identifies that inflammatogenic bacDNA utilizes LL-37 as a vehicle for blood translocation and to evade immune elimination. Additionally, bacteria may make a milieu by releasing bacDNA to utilize and resist host antimicrobial peptides as a 'trojan horse'.
细菌DNA（bacDNA）在溃疡性结肠炎（UC）和克罗恩病患者的血清中经常被发现，即便血液细菌培养呈阴性。bacDNA如何逃避免疫清除并转移至血液中仍不清楚。在此，我们表明，bacDNA通过与抗菌肽LL-37（小鼠中的Cramp）形成复合物来避免被清除，并使抗菌肽LL-37的杀菌功能失活，该复合物在与细菌或细菌产物培养后可被诱导产生。在UC患者的血浆和病变组织中发现LL-37-bacDNA复合物水平升高。LL-37-bacDNA通过诱导Th1、Th2和Th17分化以及激活Toll样受体9（TLR9）来促进炎症反应。该复合物还增加了细胞旁通透性，这可能与其炎症效应相结合，促进局部损伤以及bacDNA转移至血液中。Cramp-bacDNA加重了小鼠结肠炎的严重程度，而干扰该复合物则改善了病情。该研究表明，具有致炎作用的bacDNA利用LL-37作为血液转移的载体并逃避免疫清除。此外，细菌可能通过释放bacDNA营造一种环境，以此作为“特洛伊木马”来利用并抵抗宿主抗菌肽。
