Structural and Signaling Events Driving Aspergillus fumigatus-Induced Human Eosinophil Extracellular Trap Release.
Structural and Signaling Events Driving Aspergillus fumigatus-Induced Human Eosinophil Extracellular Trap Release.
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DOI：
10.3389/fmicb.2021.633696
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发表时间：
2021
影响因子：
5.2
通讯作者：
Neves JS
中科院分区：
文献类型：
--
作者：
Barroso MV;Gropillo I;Detoni MAA;Thompson-Souza GA;Muniz VS;Vasconcelos CRI;Figueiredo RT;Melo RCN;Neves JS
嗜酸性粒细胞是典型的参与过敏性疾病和宿主对蠕虫、真菌、细菌和病毒的免疫应答的粒细胞。白细胞释放细胞外DNA陷阱是各种感染性疾病（包括真菌感染）中对病原体的先天免疫应答的重要机制。烟曲霉是一种机会性真菌，可引起过敏性支气管肺曲霉病（ABPA），这是一种以显著嗜酸性粒细胞炎症为特征的肺部疾病。以前，我们证明了分离的人嗜酸性粒细胞在A.离体培养。这种释放是通过涉及CD 11b和Syk酪氨酸激酶的溶解性非氧化机制发生的。在这项工作中，我们揭示了不同的细胞内机制，驱动释放细胞外DNA陷阱的A。烟熏刺激的嗜酸性粒细胞。在超微结构上，我们最初观察到A.烟曲霉刺激的嗜酸性粒细胞表现出细胞外DNA陷阱细胞死亡（ETosis）的典型迹象，细胞核失去其形状（脱叶）和常染色质/异染色质区别，随后核膜破裂和ETosis释放。我们还发现，通过靶向I类PI 3 K，更具体地说是PI 3 K δ，A.烟曲霉被抑制。我们还证明了A.在真菌生存力降低的过程中，烟曲霉诱导的EkB释放依赖于Src家族、Akt、钙和p38 MAPK信号通路。有趣的是，我们发现A.烟曲霉诱导的Escherichia coli释放以独立于PAD 4组蛋白瓜氨酸的机制发生。这些发现可能有助于更好地理解在响应于A.烟曲霉，这可能会导致更好地了解ABPA的病理生理学和治疗。
Eosinophils are granulocytes classically involved in allergic diseases and in the host immune responses to helminths, fungi, bacteria and viruses. The release of extracellular DNA traps by leukocytes is an important mechanism of the innate immune response to pathogens in various infectious conditions, including fungal infections. Aspergillus fumigatus is an opportunistic fungus responsible for allergic bronchopulmonary aspergillosis (ABPA), a pulmonary disease marked by prominent eosinophilic inflammation. Previously, we demonstrated that isolated human eosinophils release extracellular DNA traps (eosinophil extracellular traps; EETs) when stimulated by A. fumigatus in vitro. This release occurs through a lytic non-oxidative mechanism that involves CD11b and Syk tyrosine kinase. In this work, we unraveled different intracellular mechanisms that drive the release of extracellular DNA traps by A. fumigatus-stimulated eosinophils. Ultrastructurally, we originally observed that A. fumigatus-stimulated eosinophils present typical signs of extracellular DNA trap cell death (ETosis) with the nuclei losing both their shape (delobulation) and the euchromatin/heterochromatin distinction, followed by rupture of the nuclear envelope and EETs release. We also found that by targeting class I PI3K, and more specifically PI3Kδ, the release of extracellular DNA traps induced by A. fumigatus is inhibited. We also demonstrated that A. fumigatus-induced EETs release depends on the Src family, Akt, calcium and p38 MAPK signaling pathways in a process in which fungal viability is dispensable. Interestingly, we showed that A. fumigatus-induced EETs release occurs in a mechanism independent of PAD4 histone citrullination. These findings may contribute to a better understanding of the mechanisms that underlie EETs release in response to A. fumigatus, which may lead to better knowledge of ABPA pathophysiology and treatment.
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影响因子：
6.1
作者：
Agarwal, R.;Chakrabarti, A.;Denning, D. W.
通讯作者：
Denning, D. W.
影响因子：
6.7
作者：
Bruns S;Kniemeyer O;Hasenberg M;Aimanianda V;Nietzsche S;Thywissen A;Jeron A;Latgé JP;Brakhage AA;Gunzer M
通讯作者：
Gunzer M
DOI：
10.1152/ajplung.00005.2012
发表时间：
2012-06-01
影响因子：
4.9
作者：
Kang, Bit Na;Ha, Sung Gil;Sriramarao, P.
通讯作者：
Sriramarao, P.
DOI：
10.1073/pnas.0900226106
发表时间：
2009-04-21
影响因子：
11.1
作者：
Guimaraes-Costa, Anderson B.;Nascimento, Michelle T. C.;Saraiva, Elvira M.
通讯作者：
Saraiva, Elvira M.
影响因子：
4.4
作者：
Denning DW;Pashley C;Hartl D;Wardlaw A;Godet C;Del Giacco S;Delhaes L;Sergejeva S
通讯作者：
Sergejeva S