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MyD88 和 CARD9 在呼吸道真菌感染期间趋化因子诱导和固有防御中的特定隔室和顺序作用。

Compartment-specific and sequential role of MyD88 and CARD9 in chemokine induction and innate defense during respiratory fungal infection.

机构信息

Infectious Disease Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America.

Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth University, Hanover, New Hampshire, United States of America.

出版信息

PLoS Pathog. 2015 Jan 26;11(1):e1004589. doi: 10.1371/journal.ppat.1004589. eCollection 2015 Jan.

Abstract

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.

摘要

烟曲霉形成无处不在的空气传播分生孢子,人类每天都会吸入。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 CARD9 和 MyD88,但定义 MyD88 和 CARD9 耦合信号在免疫激活和真菌清除中的时空模式一直难以实现。在此,我们证明 MyD88 和 CARD9 在两个离散相中并在两个细胞区室中作用,以指导趋化因子和中性粒细胞依赖性宿主防御。第一阶段依赖于 MyD88 信号转导,因为 MyD88 的遗传缺失导致中性粒细胞趋化因子 CXCL1 和 CXCL5 的诱导延迟,中性粒细胞在肺部的迁移延迟,以及呼吸道真菌感染开始时致命的肺部损伤。肺上皮细胞中 MyD88 的表达通过白细胞介素 1 受体信号恢复快速趋化因子诱导和中性粒细胞募集。外源性 CXCL1 给药可逆转 MyD88 缺陷小鼠的鼠死亡率。第二阶段主要依赖于 CARD9 信号转导,因为在辐射敏感的造血细胞中 CARD9 的遗传缺失会中断 CXCL1 和 CXCL2 的产生,并在初始 MyD88 依赖性阶段之外中断肺中性粒细胞募集。使用 CXCL2 报告小鼠,我们表明在 CARD9 依赖性募集期间,肺部浸润的中性粒细胞是 CXCL2 的主要细胞来源。尽管中性粒细胞固有型 MyD88 和 CARD9 功能对于中性粒细胞孢子的摄取和肺部杀伤是可有可无的,但当小鼠受到对于单个衔接蛋白敲除小鼠亚致死接种量的挑战时,两种衔接蛋白的全局缺失会触发迅速进展的侵袭性疾病。我们的研究结果表明,呼吸道上皮和造血区室中的不同信号转导途径部分重叠,以确保呼吸道内最佳趋化因子诱导、中性粒细胞募集和真菌清除。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d397/4306481/757a92a69f08/ppat.1004589.g001.jpg

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