Rapid Sequestration of Leishmania mexicana by Neutrophils Contributes to the Development of Chronic Lesion.
Rapid Sequestration of Leishmania mexicana by Neutrophils Contributes to the Development of Chronic Lesion.
复制标题
DOI：
10.1371/journal.ppat.1004929
复制
发表时间：
2015-05
期刊：
影响因子：
6.7
通讯作者：
Tacchini-Cottier F
中科院分区：
文献类型：
--
作者：
Hurrell BP;Schuster S;Grün E;Coutaz M;Williams RA;Held W;Malissen B;Malissen M;Yousefi S;Simon HU;Müller AJ;Tacchini-Cottier F
原生动物墨西哥利什曼原虫寄生虫在寄生虫控制不良的人类和小鼠中引起慢性非愈合性皮肤病变。防止对这种寄生虫产生保护性免疫反应的机制尚不清楚。在这里，我们提供的数据表明，寄生虫隔离的中性粒细胞是负责在小鼠的疾病进展。在感染L的几个小时内。mexicana诱导嗜中性粒细胞的局部募集，嗜中性粒细胞摄取寄生虫并形成细胞外陷阱，而不显著损害寄生虫的存活。进一步证明了L.通过活体双光子显微镜和流式细胞术分析观察到，墨西哥引起的中性粒细胞的募集损害了感染部位树突细胞的早期募集。事实上，在感染开始时，嗜中性粒细胞减少的Genista小鼠和嗜中性粒细胞耗竭的小鼠的感染证明了嗜中性粒细胞在该过程中的突出作用。此外，在血小板减少小鼠的引流淋巴结中也观察到单核细胞来源的树突状细胞增加，这与随后分泌IFN γ的T辅助细胞频率增加以及更好的寄生虫控制相关，最终导致病变完全愈合。总之，这些研究结果表明，L。Mexicana利用嗜中性粒细胞来阻断保护性免疫应答的诱导并损害对病变发展的控制。因此，我们的数据表明，这些先天免疫细胞在宿主防御中发挥了意想不到的负面作用，这表明在某些形式的皮肤利什曼病中，调节中性粒细胞募集可能是促进病变愈合的策略。利什曼原虫感染引起一系列疾病，从皮肤到内脏形式，如果不治疗是致命的。在不同的利什曼原虫物种中，墨西哥利什曼原虫引起人类慢性皮肤病变。为了研究这种疾病，我们使用了小鼠模型。感染墨西哥利什曼原虫后，包括C57 BL/6在内的大多数小鼠物种发生慢性不愈合病变。在感染后的几个小时内，中性粒细胞在当地被招募并摄入寄生虫。虽然中性粒细胞是能够使用分子库快速杀死病原体的白细胞，但包括一些但不是全部的利什曼原虫属的几种微生物能够在这些细胞内存活。在这里，我们表明，L。mexicana在感染部位促进嗜中性粒细胞的快速募集，在这些细胞内存活并利用它们。此外，嗜中性粒细胞的暂时寄生虫隔离延迟了其他白细胞如单核细胞的募集，导致针对寄生虫的保护性免疫应答的受损发展和慢性病变发展。因此，我们描述了一个以前没有预料到的致病作用，中性粒细胞在慢性病变的发展。更重要的是，我们的数据表明，在某些形式的皮肤利什曼病，调节中性粒细胞募集可能是一种策略，以促进病变愈合。
The protozoan Leishmania mexicana parasite causes chronic non-healing cutaneous lesions in humans and mice with poor parasite control. The mechanisms preventing the development of a protective immune response against this parasite are unclear. Here we provide data demonstrating that parasite sequestration by neutrophils is responsible for disease progression in mice. Within hours of infection L. mexicana induced the local recruitment of neutrophils, which ingested parasites and formed extracellular traps without markedly impairing parasite survival. We further showed that the L. mexicana-induced recruitment of neutrophils impaired the early recruitment of dendritic cells at the site of infection as observed by intravital 2-photon microscopy and flow cytometry analysis. Indeed, infection of neutropenic Genista mice and of mice depleted of neutrophils at the onset of infection demonstrated a prominent role for neutrophils in this process. Furthermore, an increase in monocyte-derived dendritic cells was also observed in draining lymph nodes of neutropenic mice, correlating with subsequent increased frequency of IFNγ-secreting T helper cells, and better parasite control leading ultimately to complete healing of the lesion. Altogether, these findings show that L. mexicana exploits neutrophils to block the induction of a protective immune response and impairs the control of lesion development. Our data thus demonstrate an unanticipated negative role for these innate immune cells in host defense, suggesting that in certain forms of cutaneous leishmaniasis, regulating neutrophil recruitment could be a strategy to promote lesion healing. Infection with the protozoan Leishmania parasites causes a spectrum of diseases ranging from cutaneous to visceral forms that are fatal if left untreated. Among the different Leishmania species, Leishmania mexicana causes chronic cutaneous lesions in humans. To study this disease, we used a murine model. Following infection with Leishmania mexicana, most mouse species including C57BL/6 develop chronic non-healing lesion. Within hours of infection, neutrophils are recruited locally and they ingest the parasites. Although neutrophils are leukocytes that are able to rapidly kill pathogens using an arsenal of molecules, several microorganisms including some, but not all, Leishmania species are able to survive within these cells. Here, we show that L. mexicana elicits the rapid recruitment of neutrophils at the site of infection, survives within these cells and uses them to its advantage. Furthermore, transient parasite sequestration by neutrophils delays recruitment of other leukocytes such as monocytes, contributing to the impaired development of a protective immune response against the parasite and chronic lesion development. Thus, we describe a previously unanticipated pathogenic role for neutrophils in chronic lesion development. More importantly, our data suggest that in certain forms of cutaneous leishmaniasis, regulating neutrophil recruitment could be a strategy to promote lesion healing.
登录
查看更多内容
DOI：
10.1084/jem.188.10.1941
发表时间：
1998-11-16
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Belkaid Y;Kamhawi S;Modi G;Valenzuela J;Noben-Trauth N;Rowton E;Ribeiro J;Sacks DL
通讯作者：
Sacks DL
感染期间淋巴结中中性粒细胞迁移的动态。
影响因子：
32.4
作者：
Chtanova, Tatyana;Schaeffer, Marie;Han, Seong-Ji;van Dooren, Giel G.;Nollmann, Marcelo;Herzmark, Paul;Chan, Shiao Wei;Satija, Harshita;Camfield, Kristin;Aaron, Holly;Striepen, Boris;Robey, Ellen A.
通讯作者：
Robey, Ellen A.
墨西哥利什曼病感染对树突状细胞信号传导和功能的影响
影响因子：
3.8
作者：
Contreras I;Estrada JA;Guak H;Martel C;Borjian A;Ralph B;Shio MT;Fournier S;Krawczyk CM;Olivier M
通讯作者：
Olivier M
影响因子：
2.2
作者：
Belloso, SP;Saloma, PO;García-Zepeda, E
通讯作者：
García-Zepeda, E
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.