Lu Yingying, Jiang Hong, Li Bingjue, Cao Luxi, Shen Qixia, Yi Weiwei, Ju Zhenyu, Chen Liangliang, Han Fei, Appelgren Daniel, Segelmark Mårten, de Buhr Nicole, von Köckritz-Blickwede Maren, Chen Jianghua
Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China.
Kidney Disease Immunology Laboratory, The Third Grade Laboratory, State Administration of Traditional Chinese Medicine of PR China, Hangzhou 310003, China.
Ann Transl Med. 2020 Mar;8(6):357. doi: 10.21037/atm.2020.02.130.
Small vessel vasculitis (SVV) is a group of systemic autoimmune diseases that are mediated by neutrophil extracellular traps (NETs) in response to cathelicidin LL37, an aging molecular marker, which could be induced by telomere dysfunction. Therefore, in this study, we evaluated the hypothesis that telomere dysfunction in neutrophils may promote SVV via an LL37-NETs-dependent mechanism.
We contrasted the release of neutrophil NETs from mice with telomere dysfunction, mice with DNA damage and wide-type mice. Neutrophil telomere length, the expression of LL37, and the formation of NETs were measured in SVV patients and healthy controls (HCs). The co-expression of γH2AX, LL37, and NETs were detected in SVV patients to evaluate the association of the immune aging of neutrophils and pro-inflammatory conditions. LL37 inhibitor was used to verify its key role in NETs release in SVV patients and DNA damage mice.
We found that NETs were over-induced by telomere dysfunction and DNA damage in mice, which may be associated with a marked increase in LL37. For patients with SVV, telomeres in neutrophils were significantly shortened, which was also associated with higher levels of LL37 and NETs. Inhibition of LL37 reduced the NETs released from neutrophils.
Taken together, the results of these studies suggest that dysfunction of telomeres may promote SVV through the mechanism of LL37-dependent NETs. Thus, targeting the LL37-NETs may be a novel therapy for SVV.
小血管炎（SVV）是一组系统性自身免疫性疾病，由中性粒细胞胞外诱捕网（NETs）介导，其对衰老分子标志物cathelicidin LL37产生反应，而LL37可由端粒功能障碍诱导产生。因此，在本研究中，我们评估了中性粒细胞端粒功能障碍可能通过LL37-NETs依赖机制促进小血管炎的这一假说。
我们对比了端粒功能障碍小鼠、DNA损伤小鼠和野生型小鼠中性粒细胞NETs的释放情况。在小血管炎患者和健康对照者（HCs）中测量中性粒细胞端粒长度、LL37的表达及NETs的形成。在小血管炎患者中检测γH2AX、LL37和NETs的共表达情况，以评估中性粒细胞免疫衰老与促炎状态之间的关联。使用LL37抑制剂来验证其在小血管炎患者和DNA损伤小鼠NETs释放中的关键作用。
我们发现端粒功能障碍和DNA损伤可在小鼠中过度诱导NETs产生，这可能与LL37的显著增加有关。对于小血管炎患者，中性粒细胞中的端粒明显缩短，这也与更高水平的LL37和NETs有关。抑制LL37可减少中性粒细胞释放的NETs。
综上所述，这些研究结果表明端粒功能障碍可能通过LL37依赖的NETs机制促进小血管炎。因此，针对LL37-NETs可能是小血管炎的一种新疗法。
