中性粒细胞外陷阱可提高仙台病毒诱导的哮喘表型的早期炎症反应
2016/10/09
摘要
童年时期副粘病毒感染与哮喘发病率显著增加相关。在小鼠中，副流感病毒I型，即仙台病毒（Sev）感染，会导致有限的毛细支气管炎并伴随持续性哮喘。我们先前已经表明半胱氨酸蛋白酶的二肽基肽酶（DPPI）的缺乏能抑制急性肺部炎症反应和Sev诱导的哮喘后续表型。野生型中性粒细胞过继转移到DPPI缺陷小鼠恢复白细胞涌入、急性炎症反应、以及随后的粘液细胞化生，伴随Sev诱发的哮喘表型。然而，DPPI 缺陷的中性粒细胞通过何种确切的机制促进Sev感染后哮喘的发展仍然是未知的。我们推测，中性粒细胞在Sev感染之后招募到进肺泡空间变成了中性粒细胞外陷阱（NETs）来扩大炎症级联反应，最终导致其在最终哮喘表型上积累。事实上，我们发现，Sev感染与中性粒细胞外陷阱（NETs）在肺里的形成和DNA络合髓过氧化物酶在肺泡空间和血浆中的释放有关。DNA络合髓过氧化物酶在肺泡空间和血浆中的释放在感染后2天达到高峰。DPPI的缺乏显著衰减了Sev诱导的中性粒细胞外陷阱体内和体外的形成。此外，DNase 1合用，能清除中性粒细胞外陷阱，或抑制肽酰基精氨酸脱亚胺酶4（PAD4），是中性粒细胞外陷阱形成的重要介质，可抑制Sev感染引起的早期炎症反应。最后，中性粒细胞外陷阱可使得骨髓来源的细胞释放细胞因子来放大炎症级联反应。
关键词：中性粒细胞外陷阱；仙台病毒诱导的哮喘；细胞因子；二肽基肽酶Ⅰ；中性粒细胞
（杨冬 审校）
FrontImmunol.2016Aug26;7:325. doi: 10.3389/fimmu.2016.00325. eCollection 2016.
Neutrophil Extracellular Traps Enhance Early Inflammatory Response in Sendai Virus-Induced AsthmaPhenotype.
Akk A1, Springer LE1, Pham CT1.
Author information
Abstract
Paramyxoviral infection in childhood has been linked to a significant increased rate of asthma development. In mice, paramyxoviral infection with the mouse parainfluenza virus type I, Sendai virus (Sev), causes a limited bronchiolitis followed by persistent asthma traits. We have previously shown that the absence of cysteine protease dipeptidyl peptidase I (DPPI) dampened the acute lung inflammatory response and the subsequentasthma phenotype induced by Sev. Adoptive transfer of wild-type neutrophils into DPPI-deficient mice restored leukocyte influx, the acute cytokine response, and the subsequent mucous cell metaplasia that accompanied Sev-induced asthma phenotype. However, the exact mechanism by which DPPI-sufficient neutrophils promote asthma development following Sev infection is still unknown. We hypothesize that neutrophils recruited to the alveolar space following Sev infection elaborate neutrophil extracellular traps (NETs) that propagate the inflammatory cascade, culminating in the eventual asthma phenotype. Indeed, we found that Sev infection was associated with NET formation in the lung and release of cell-free DNA complexed to myeloperoxidase in the alveolar space and plasma that peaked on day 2 post infection. Absence of DPPI significantly attenuated Sev-induced NET formation in vivo and in vitro. Furthermore, concomitant administration of DNase 1, which dismantled NETs, or inhibition of peptidylarginine deiminase 4 (PAD4), an essential mediator of NET formation, suppressed the early inflammatory responses to Sev infection. Lastly, NETs primed bone marrow-derived cells to release cytokines that can amplify the inflammatory cascade.
KEYWORDS:NETs; Sendai virus-induced asthma; cytokines; dipeptidyl peptidase I; neutrophils
FrontImmunol.2016Aug26;7:325. doi: 10.3389/fimmu.2016.00325. eCollection 2016.
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在哮喘和慢性阻塞性肺疾病中microRNA表达差异的初步研究
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在过敏性哮喘和鼻炎小鼠模型中的慢性超重独立效应
