Notch regulates Histoplasma capsulatum clearance in mouse lungs during innate and adaptive immune response phases in primary infection.
Notch regulates Histoplasma capsulatum clearance in mouse lungs during innate and adaptive immune response phases in primary infection.
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DOI：
10.1002/jlb.4a1221-743r
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发表时间：
2022-11
影响因子：
5.5
通讯作者：
Deepe, George S., Jr.
中科院分区：
文献类型：
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作者：
Huang, Shuo;Deepe, George S., Jr.
病原性真菌荚膜组织胞浆菌的清除需要先天免疫和适应性免疫之间的合作。由于这种微生物被吸入，肺巨噬细胞和树突状细胞（DC）是第一道防线。此外，DC作为APC驱动1型Th细胞产生IFNγ，这有助于最终消除H。荚膜在这项研究中，我们探讨了Notch信号在宿主防御的重要性，使用小鼠肺组织胞浆菌病模型。我们发现，在肺和淋巴结感染后，吞噬细胞和IFNγ+ CD 4 + T细胞上的Notch配体（NL）和Notch受体（NR）上调。为了确定Notch对感染过程的影响，我们使用了γ分泌酶抑制剂（GSI）LY-411，575，它抑制NR下游信号传导。当在感染时或感染后7天给予该化合物时，该化合物损害真菌清除。然而，GSI不影响具有预先存在的免疫力的小鼠中的真菌清除。减弱的宿主防御与单核细胞衍生的DC的分化和成熟降低以及单核细胞衍生的巨噬细胞和肺泡巨噬细胞向M2极化升高相关。我们的研究揭示了Notch信号在维持对这种感染因子的控制方面的关键性质。Notch信号传导决定树突状细胞和单核细胞/巨噬细胞在真菌感染中的功能。
The clearance of the pathogenic fungus, Histoplasma capsulatum, requires cooperation between innate and adaptive immunity. Since this organism is inhaled, lung macrophages and dendritic cells (DCs) are the first lines of defense. Moreover, DCs act as APCs to drive the education of type 1 Th cells to produce IFNγ, which contributes to the final elimination of H. capsulatum. In this study, we explored the importance of Notch signaling in host defenses using a mouse model of pulmonary histoplasmosis. We found up‐regulation of Notch ligands (NLs) and Notch receptors (NRs) on phagocytes and IFNγ+ CD4+ T cells upon infection in lungs and lymph nodes. To ascertain the influence of Notch on the course of infection, we used a gamma‐secretase inhibitor (GSI), LY‐411,575, which inhibits NR downstream signaling. This compound impaired fungal clearance when given at the time of infection or 7 days after infection. However, GSI did not impact fungal clearance in mice with preexisting immunity. The dampened host defenses were associated with reduced differentiation and maturation of monocyte‐derived DCs and elevatmonocyte‐derived macrophage and alveolar macrophage polarization to M2. Our study reveals the critical nature of Notch signaling in maintaining control of this infectious agent. Notch signaling dictates the function of dendritic cells and monocytes/macrophages in fungal infection.