Compartment-specific and sequential role of MyD88 and CARD9 in chemokine induction and innate defense during respiratory fungal infection.
Compartment-specific and sequential role of MyD88 and CARD9 in chemokine induction and innate defense during respiratory fungal infection.
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DOI：
10.1371/journal.ppat.1004589
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发表时间：
2015-01
期刊：
影响因子：
6.7
通讯作者：
Hohl TM
中科院分区：
文献类型：
--
作者：
Jhingran A;Kasahara S;Shepardson KM;Junecko BA;Heung LJ;Kumasaka DK;Knoblaugh SE;Lin X;Kazmierczak BI;Reinhart TA;Cramer RA;Hohl TM
烟曲霉形成无处不在的空气分生孢子，人类每天吸入。虽然呼吸道真菌感染通过C型凝集素、Toll样和白细胞介素-1家族受体信号激活衔接蛋白CARD 9和MyD 88，但在免疫激活和真菌清除中定义MyD 88和CARD 9偶联信号的时间和空间模式一直难以实现。在此，我们证明了MyD 88和CARD 9在两个离散的阶段和两个细胞隔室中起作用，以指导趋化因子和嗜中性粒细胞依赖性宿主防御。第一阶段依赖于MyD 88信号传导，因为MyD 88的基因缺失导致中性粒细胞趋化因子CXCL 1和CXCL 5的延迟诱导，延迟的中性粒细胞肺运输，以及呼吸道真菌感染发作时的致命性肺损伤。MyD 88在肺上皮细胞中的表达通过白细胞介素-1受体信号传导恢复快速趋化因子诱导和中性粒细胞募集。外源性CXCL 1给药逆转MyD 88缺陷小鼠的小鼠死亡率。第二阶段主要依赖于CARD 9信号传导，因为放射敏感性造血细胞中CARD 9的基因缺失中断了CXCL 1和CXCL 2的产生以及肺中性粒细胞募集超过初始MyD 88依赖性阶段。使用CXCL 2报告小鼠，我们表明，肺浸润中性粒细胞代表的主要细胞来源的CXCL 2在CARD 9依赖性招聘。尽管嗜中性粒细胞固有的MyD 88和CARD 9功能对于肺中的嗜中性粒细胞分生孢子摄取和杀伤是不利的，但是当用对于单个衔接蛋白敲除小鼠亚致死的接种物攻击小鼠时，两种衔接蛋白的全局缺失触发快速进行性侵袭性疾病。我们的研究结果表明，不同的信号转导通路在呼吸道上皮和造血隔室部分重叠，以确保最佳的趋化因子诱导，中性粒细胞的招聘，和真菌清除呼吸道内。我们对肺中上皮细胞和造血细胞如何协调对吸入的真菌分生孢子（孢子）的免疫的理解仍然有限。霉菌烟曲霉是免疫功能低下患者感染性死亡的主要原因。宿主对A.烟曲霉感染涉及两种宿主信号转导子MyD 88和CARD 9的激活，导致中性粒细胞募集到感染部位。在这项研究中，我们定义了MyD 88和CARD 9偶联信号如何在上皮和造血区室中调节嗜酸性粒细胞介导的对A.烟熏。我们的研究支持一个两阶段模型，其中MyD 88在上皮细胞中的激活，通过白细胞介素-1受体，支持快速诱导嗜中性粒细胞招募趋化因子。这个过程对于中性粒细胞募集的第一阶段至关重要。在MyD 88缺陷小鼠中观察到的死亡率可以通过向感染的气道给予称为CXCL 1的趋化因子而显著逆转。中性粒细胞募集的第二阶段由造血细胞中的CARD 9信号传导启动。趋化因子诱导和中性粒细胞募集两个阶段的缺失显著增加了小鼠对组织浸润性疾病的易感性。总之，我们的研究定义了一个事件的时间序列，由肺上皮细胞中的白细胞介素-1受体/MyD 88信号传导启动，并由造血细胞中的CARD 9信号传导传播，诱导对吸入性真菌分生孢子的保护性免疫。
Aspergillus fumigatus forms ubiquitous airborne conidia that humans inhale on a daily basis. Although respiratory fungal infection activates the adaptor proteins CARD9 and MyD88 via C-type lectin, Toll-like, and interleukin-1 family receptor signals, defining the temporal and spatial pattern of MyD88- and CARD9-coupled signals in immune activation and fungal clearance has been difficult to achieve. Herein, we demonstrate that MyD88 and CARD9 act in two discrete phases and in two cellular compartments to direct chemokine- and neutrophil-dependent host defense. The first phase depends on MyD88 signaling because genetic deletion of MyD88 leads to delayed induction of the neutrophil chemokines CXCL1 and CXCL5, delayed neutrophil lung trafficking, and fatal pulmonary damage at the onset of respiratory fungal infection. MyD88 expression in lung epithelial cells restores rapid chemokine induction and neutrophil recruitment via interleukin-1 receptor signaling. Exogenous CXCL1 administration reverses murine mortality in MyD88-deficient mice. The second phase depends predominately on CARD9 signaling because genetic deletion of CARD9 in radiosensitive hematopoietic cells interrupts CXCL1 and CXCL2 production and lung neutrophil recruitment beyond the initial MyD88-dependent phase. Using a CXCL2 reporter mouse, we show that lung-infiltrating neutrophils represent the major cellular source of CXCL2 during CARD9-dependent recruitment. Although neutrophil-intrinsic MyD88 and CARD9 function are dispensable for neutrophil conidial uptake and killing in the lung, global deletion of both adaptor proteins triggers rapidly progressive invasive disease when mice are challenged with an inoculum that is sub-lethal for single adapter protein knockout mice. Our findings demonstrate that distinct signal transduction pathways in the respiratory epithelium and hematopoietic compartment partially overlap to ensure optimal chemokine induction, neutrophil recruitment, and fungal clearance within the respiratory tract. Our understanding of how epithelial and hematopoietic cells in the lung coordinate immunity against inhaled fungal conidia (spores) remains limited. The mold Aspergillus fumigatus is a major cause of infectious mortality in immune compromised patients. Host defense against A. fumigatus involves the activation of two host signal transducers, MyD88 and CARD9, leading to neutrophil recruitment to the infection site. In this study, we define how MyD88- and CARD9-coupled signals operate in epithelial and hematopoietic compartments to regulate neutrophil-mediated defense against A. fumigatus. Our studies support a two-stage model in which MyD88 activation in epithelial cells, via the interleukin-1 receptor, supports the rapid induction of neutrophil-recruiting chemokines. This process is essential for the first phase of neutrophil recruitment. Mortality observed in MyD88-deficient mice can be significantly reversed by administration of a chemokine termed CXCL1 to infected airways. The second phase of neutrophil recruitment is initiated by CARD9 signaling in hematopoietic cells. Loss of both phases of chemokine induction and neutrophil recruitment dramatically increases murine susceptibility to tissue-invasive disease. In sum, our study defines a temporal sequence of events, initiated by interleukin-1 receptor/MyD88 signaling in the pulmonary epithelium and propagated by CARD9 signaling in hematopoietic cells, that induces protective immunity against inhaled fungal conidia.
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DOI：
10.4049/jimmunol.0903843
发表时间：
2010-11-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Cai S;Batra S;Lira SA;Kolls JK;Jeyaseelan S
通讯作者：
Jeyaseelan S
DOI：
10.1056/nejmoa0802629
发表时间：
2008-10-23
期刊：
The New England journal of medicine
影响因子：
--
作者：
Bochud PY;Chien JW;Marr KA;Leisenring WM;Upton A;Janer M;Rodrigues SD;Li S;Hansen JA;Zhao LP;Aderem A;Boeckh M
通讯作者：
Boeckh M
Interleukin-1家族：回到未来。
影响因子：
32.4
作者：
Garlanda C;Dinarello CA;Mantovani A
通讯作者：
Mantovani A
影响因子：
3.1
作者：
Fallert, BA;Reinhart, TA
通讯作者：
Reinhart, TA
影响因子：
6.7
作者：
Gresnigt MS;Bozza S;Becker KL;Joosten LA;Abdollahi-Roodsaz S;van der Berg WB;Dinarello CA;Netea MG;Fontaine T;De Luca A;Moretti S;Romani L;Latge JP;van de Veerdonk FL
通讯作者：
van de Veerdonk FL