Extramedullary myelopoiesis in malaria depends on mobilization of myeloid-restricted progenitors by IFN-γ induced chemokines.
Extramedullary myelopoiesis in malaria depends on mobilization of myeloid-restricted progenitors by IFN-γ induced chemokines.
复制标题
DOI：
10.1371/journal.ppat.1003406
复制
发表时间：
2013
期刊：
影响因子：
6.7
通讯作者：
Potocnik AJ
中科院分区：
文献类型：
--
作者：
Belyaev NN;Biró J;Langhorne J;Potocnik AJ
各种急性细菌和寄生虫感染的解决关键依赖于刺激骨髓生成，导致髓外造血。在这里，我们报告的最早的骨髓限制性祖细胞在急性感染的啮齿动物疟疾寄生虫，疟原虫夏氏疟原虫的分离。这些感染诱导的髓系祖细胞从骨髓（BM）中的快速消失等同于该器官中功能性髓系潜能的收缩。Toll样受体信号传导的完全遗传失活不影响BM骨髓细胞生成的损失。IFN-γ信号转导的失活完全消除了BM骨髓祖细胞的收缩。Ifngr 1-null和对照BM的辐射嵌合体显示，抗辐射基质隔室中的IFN-γ信号传导对于早期髓系祖细胞的损失至关重要。系统性IFN-γ触发C-C基序配体趋化因子CCL 2和CCL 7的分泌，导致早期髓样定向祖细胞由其共同受体CCR 2介导从骨髓中流出。骨髓祖细胞的动员以CCR 2依赖的方式启动了脾脏中的髓外骨髓生成，导致急性疟疾期间骨髓生成增加。与缺乏CCR 2时脾骨髓生成的缺乏一致，我们观察到在疟疾感染的CCR 2缺陷宿主中寄生虫血症的显著持续性。我们的研究结果揭示了激活的免疫系统如何动员早期骨髓祖细胞，从而在脾脏中瞬时建立骨髓生成，以遏制和解决局部感染。人和大多数动物模型中的疟疾伴有脾肿大。同时，脾脏是控制寄生虫血症消退的主要器官。这个过程最初主要依赖于先天免疫系统，并需要增加骨髓细胞的产生。我们研究了在用夏氏疟原虫感染小鼠期间骨髓（BM）LIN−细胞（包括造血干细胞和祖细胞）的数量，并观察到显着减少。使用早期骨髓限制性祖细胞的精确定义，我们可以证明疟疾中这些细胞的损失等同于BM骨髓生成的收缩。由于基质细胞上IFN-γ受体的缺乏足以阻断这种收缩，我们研究了IFN-γ对趋化因子分泌的影响。我们观察到CCL 2/CCL 7血清水平的巨大上调和在峰值寄生虫血症时BM中Ccl 2/Ccl 7转录的增加。早期髓系祖细胞从BM中的排出严重依赖于趋化因子受体CCR 2。它们的动员导致脾脏中的髓外骨髓增生，这有助于清除寄生虫感染的红细胞。我们的研究确定了导致在疟疾小鼠模型中建立脾骨髓生成的各种细胞类型的分子信号和相互作用。
Resolution of a variety of acute bacterial and parasitic infections critically relies on the stimulation of myelopoiesis leading in cases to extramedullary hematopoiesis. Here, we report the isolation of the earliest myeloid-restricted progenitors in acute infection with the rodent malaria parasite, Plasmodium chabaudi. The rapid disappearance of these infection-induced myeloid progenitors from the bone marrow (BM) equated with contraction of the functional myeloid potential in that organ. The loss of BM myelopoiesis was not affected by the complete genetic inactivation of toll-like receptor signaling. De-activation of IFN-γ signaling completely abrogated the contraction of BM myeloid progenitors. Radiation chimeras of Ifngr1-null and control BM revealed that IFN-γ signaling in an irradiation-resistant stromal compartment was crucial for the loss of early myeloid progenitors. Systemic IFN-γ triggered the secretion of C-C motif ligand chemokines CCL2 and CCL7 leading to the egress of early, myeloid-committed progenitors from the bone marrow mediated by their common receptor CCR2. The mobilization of myeloid progenitors initiated extramedullary myelopoiesis in the spleen in a CCR2-dependent manner resulting in augmented myelopoiesis during acute malaria. Consistent with the lack of splenic myelopoiesis in the absence of CCR2 we observed a significant persistence of parasitemia in malaria infected CCR2-deficient hosts. Our findings reveal how the activated immune system mobilizes early myeloid progenitors out of the BM thereby transiently establishing myelopoiesis in the spleen in order to contain and resolve the infection locally. Malaria in man and in most animal models is accompanied by splenomegaly. At the same time, the spleen is the main organ for the control resolution of the parasitemia. This process initially depends mostly on the innate immune system and requires increased production of myeloid cells. We investigated the number of bone marrow (BM) LIN− cells which includes hematopoietic stem cells and progenitors during infection of mice with Plasmodium chabaudi and observed a significant reduction. Using a refined definition for early myeloid-restricted progenitors we could show that the loss of these cells in malaria equated with contraction of BM myelopoiesis. Since absence of IFN-γ receptor on stromal cells was sufficient to block this contraction we investigated the effect of IFN-γ on chemokine secretion. We observed a huge upregulation of CCL2/CCL7 serum levels and an increase in Ccl2/Ccl7 transcription in the BM at peak parasitemia. Egress from the BM of early myeloid progenitors was critically dependent on the chemokine receptor CCR2. Their mobilization resulted in extramedullary myelopopiesis in the spleen which contributed to the clearance of parasite-infected erythrocytes. Our study defined the molecular signals and interaction of various cell types leading to the establishment of splenic myelopoiesis in a mouse model of malaria.
登录
查看更多内容
DOI：
10.4049/jimmunol.1001893
发表时间：
2011-01-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
MacNamara KC;Oduro K;Martin O;Jones DD;McLaughlin M;Choi K;Borjesson DL;Winslow GM
通讯作者：
Winslow GM
影响因子：
2.2
作者：
Favre, N;Ryffel, B;Rudin, W
通讯作者：
Rudin, W
影响因子：
23.9
作者：
Haug, Jeffrey S.;He, Xi C.;Li, Linheng
通讯作者：
Li, Linheng
影响因子：
64.5
作者：
Adolfsson, J;Månsson, R;Jacobsen, SEW
通讯作者：
Jacobsen, SEW
影响因子：
5.3
作者：
Belmadani, A;Tran, PB;Miller, RJ
通讯作者：
Miller, RJ