Type I interferon signaling regulates Ly6C(hi) monocytes and neutrophils during acute viral pneumonia in mice.
Type I interferon signaling regulates Ly6C(hi) monocytes and neutrophils during acute viral pneumonia in mice.
复制标题
DOI：
10.1371/journal.ppat.1001304
复制
发表时间：
2011-02
期刊：
影响因子：
6.7
通讯作者：
Kweon MN
中科院分区：
文献类型：
--
作者：
Seo SU;Kwon HJ;Ko HJ;Byun YH;Seong BL;Uematsu S;Akira S;Kweon MN
I型干扰素（IFN-I）在造血干细胞的稳态中起关键作用，并影响中性粒细胞向炎症部位的内流。流感感染后，IFN-I受体敲除（Ifnar1−/−）小鼠肺部Ly6Chi单核细胞浸润出现明显缺陷（A/PR/8/34, H1N1）。野生型（WT）小鼠的Ly6Chi单核细胞是MCP-1的主要产生者，而Ifnar1 - / -小鼠的Ly6Cint单核细胞主要产生中性粒细胞内流的KC。因此，Ifnar1−/−小鼠在流感感染后比WT小鼠募集更多的中性粒细胞。IFNAR1阻断抗体对体外培养的WT骨髓（BM）细胞不能分化为Ly6Chi单核细胞。通过使用BM嵌合小鼠（WT BM进入Ifnar1−/−，反之亦然），我们证实造血细胞中的IFN-I信号对于Ly6Chi单核细胞的产生是必需的。值得注意的是，与流感感染的Ifnar1 - / -小鼠相比，重组的WT BM重组的Ly6Chi单核细胞数量增加的Ifnar1 - / -嵌合小鼠存活时间更长。相比之下，接受Ifnar1 - / - BM细胞的WT小鼠的死亡率高于接受WT BM细胞的WT小鼠，Ifnar1 - / - BM细胞具有替代Ly6Cint单核细胞和增加中性粒细胞的数量。总的来说，这些数据表明，IFN-I通过控制肺中的单核细胞和中性粒细胞，有助于抵抗流感感染。I型干扰素（IFN-I）最初被报道为一种干扰流感病毒复制的分子。各种IFN-I诱导的抗病毒蛋白有助于抑制病毒的复制和传播。因此，IFN-I信号的丢失会减弱抗病毒反应并加重疾病。最近的研究表明ifn - 1可能在造血中起作用，随后可能对感染部位的免疫细胞反应产生影响。事实上，IFN-I信号缺陷小鼠已被证明会产生异常的细胞群。本研究的目的是阐明IFN-I信号在单核细胞和中性粒细胞调节中的机制。我们发现IFN-I直接参与单核细胞的分化，IFN-I信号的缺失使小鼠产生基因谱明显不同的单核细胞。我们发现单核细胞是进一步募集单核细胞的趋化因子的重要来源，但ifn - i缺陷的单核细胞产生中性粒细胞募集的趋化因子。结果，缺乏IFN-I信号的小鼠募集了更多的中性粒细胞，并减少了选择性生成的单核细胞的数量。因此，我们的研究结果表明，真正的单核细胞分化（需要IFN-I信号传导）对于控制中性粒细胞和保护小鼠免受流感病毒感染至关重要。
Type I interferon (IFN-I) plays a critical role in the homeostasis of hematopoietic stem cells and influences neutrophil influx to the site of inflammation. IFN-I receptor knockout (Ifnar1 −/−) mice develop significant defects in the infiltration of Ly6Chi monocytes in the lung after influenza infection (A/PR/8/34, H1N1). Ly6Chi monocytes of wild-type (WT) mice are the main producers of MCP-1 while the alternatively generated Ly6Cint monocytes of Ifnar1 −/− mice mainly produce KC for neutrophil influx. As a consequence, Ifnar1 −/− mice recruit more neutrophils after influenza infection than do WT mice. Treatment of IFNAR1 blocking antibody on the WT bone marrow (BM) cells in vitro failed to differentiate into Ly6Chi monocytes. By using BM chimeric mice (WT BM into Ifnar1 −/− and vice versa), we confirmed that IFN-I signaling in hematopoietic cells is required for the generation of Ly6Chi monocytes. Of note, WT BM reconstituted Ifnar1 −/− chimeric mice with increased numbers of Ly6Chi monocytes survived longer than influenza-infected Ifnar1 −/− mice. In contrast, WT mice that received Ifnar1 −/− BM cells with alternative Ly6Cint monocytes and increased numbers of neutrophils exhibited higher mortality rates than WT mice given WT BM cells. Collectively, these data suggest that IFN-I contributes to resistance of influenza infection by control of monocytes and neutrophils in the lung. Type I interferon (IFN-I) was originally reported as a molecule that interferes with influenza virus replication. Various IFN-I inducible antiviral proteins contribute to dampening virus replication and dissemination. Thus, loss of IFN-I signaling attenuates antiviral response and aggravates disease. Recent studies suggest the possible role of IFN-I in hematopoiesis, which subsequently might have an effect on the immune cell response at the site of infection. Indeed, IFN-I signaling-defective mice have been shown to develop aberrant cell populations. The aim of this current study was to clarify the mechanisms of IFN-I signaling in the regulation of monocytes and neutrophils. We show that IFN-I is directly involved in monocyte differentiation and that loss of IFN-I signaling allows mice to generate monocytes whose gene profile is significantly different. We found that monocytes are an important source of chemokines for further monocyte recruitment, but IFN-I-defective monocytes produce chemokines for neutrophil recruitment. As a result, mice lacking IFN-I signaling recruit more neutrophils and a reduced number of alternatively generated monocytes. Thus, our findings indicate that authentic monocyte differentiation, which requires IFN-I signaling, is critical in controlling neutrophils and protecting mice against influenza virus infection.
登录
查看更多内容
影响因子：
30.3
作者：
Hermesh T;Moltedo B;Moran TM;López CB
通讯作者：
López CB
影响因子：
30.3
作者：
Hohl TM;Rivera A;Lipuma L;Gallegos A;Shi C;Mack M;Pamer EG
通讯作者：
Pamer EG
影响因子：
4.4
作者：
Jia, Ting;Leiner, Ingrid;Pamer, Eric G.
通讯作者：
Pamer, Eric G.
影响因子：
25.7
作者：
Craxì, A;Di Bona, D;Cammà, C
通讯作者：
Cammà, C
影响因子：
64.8
作者：
Bouchon, A;Facchetti, F;Colonna, M
通讯作者：
Colonna, M