Telomere Dysfunction Promotes Small Vessel Vasculitis Via The LL37-NETs-dependent Mechanism

ObjectivesSmall vessel vasculitis(SVV)is a systemic autoimmune inflammatory disease and is mediated by neutrophil extracellular traps(NETs)in response to LL37,an aging molecule.We previously found that telomere dysfunction induced LL37.In this study we tested the hypothesis that telomere dysfunction may promote SW via the LL37-NETs-dependent mechanism.MethodsWe used 12-month-old fourth-generation Terc gene knockout mice as the premature aging group,12-month-old wild-type mice(WT)as the same age control group,24-month-old wild-type mice as the same aging state control group,to explore the effects of telomere dysfunction on the release of NETs.We make DNA damage of neutrophils from 2-month-old WT mice by irradiation,to explore the effects of DNA damage on the release of NETs.We compared telomere length,NETs and LL37 expression levels of neutrophils in SVV patients with renal impairment and healthy controls,to explore the role of neutrophil senescence with telomere shortening and NETs release in SVV.We conduct in vitro experiments to observe the difference of NETs release in the disease group and the healthy control group and used LL37 inhibitor Aprotinin to explore the NETs release mechanism of senescent neutrophils from SVW.ResultsWe 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 SVV patients with renal impairment,telomeres in neutrophils were significantly shortened,which was also associated with higher levels of LL37 and NETs in circulation.At the same time,telomeres were shorterned in the infiltrated neutrophils in renal tissue of S W patients with renal impairment,accompanied with increased levels of LL37 and NETs in the tissue.In addition,senescent neutronphils from SW patients produced more NETs in vitro,and this process could be inhibited by inhibitors of LL37.ConclusionTaken together,results from these studies suggest that telomere dysfunction may promote SVV via the LL37-dependent NETs mechanism.Thus,targeting the LL37-NETs may represent a novel therapy for SVV.