Neither classical nor alternative macrophage activation is required for Pneumocystis clearance during immune reconstitution inflammatory syndrome.
Neither classical nor alternative macrophage activation is required for Pneumocystis clearance during immune reconstitution inflammatory syndrome.
复制标题
在免疫重建炎症综合征期间，肺孢子虫清除不需要经典或替代巨噬细胞激活。
DOI：
10.1128/iai.00763-15
复制
发表时间：
2015
影响因子：
3.1
通讯作者：
Wright,TerryW
中科院分区：
文献类型：
--
作者：
Zhang,Zhuo-Qian;Wang,Jing;Hoy,Zachary;Keegan,Achsah;Bhagwat,Samir;Gigliotti,Francis;Wright,TerryW
Pneumocystis is a respiratory fungal pathogen that causes pneumonia (Pneumocystis pneumonia [PcP]) in immunocompromised patients. Alveolar macrophages are critical effectors for CD4+T cell-dependent clearance of Pneumocystis, and previous studies found that alternative macrophage activation accelerates fungal clearance during PcP-related immune reconstitution inflammatory syndrome (IRIS). However, the requirement for either classically or alternatively activated macrophages for Pneumocystis clearance has not been determined. Therefore, RAG2−/−mice lacking either the interferon gamma (IFN-γ) receptor (IFN-γR) or interleukin 4 receptor alpha (IL-4Rα) were infected with Pneumocystis. These mice were then immune reconstituted with wild-type lymphocytes to preserve the normal T helper response while preventing downstream effects of Th1 or Th2 effector cytokines on macrophage polarization. As expected, RAG2−/−mice developed severe disease but effectively cleared Pneumocystis and resolved IRIS. Neither RAG/IFN-γR−/−nor RAG/IL-4Rα−/−mice displayed impaired Pneumocystis clearance. However, RAG/IFN-γR−/−mice developed a dysregulated immune response, with exacerbated IRIS and greater pulmonary function deficits than those in RAG2 and RAG/IL-4Rα−/−mice. RAG/IFN-γR−/−mice had elevated numbers of lung CD4+T cells, neutrophils, eosinophils, and NK cells but severely depressed numbers of lung CD8+T suppressor cells. Impaired lung CD8+T cell responses in RAG/IFN-γR−/−mice were associated with elevated lung IFN-γ levels, and neutralization of IFN-γ restored the CD8 response. These data demonstrate that restricting the ability of macrophages to polarize in response to Th1 or Th2 cytokines does not impair Pneumocystis clearance. However, a cell type-specific IFN-γ/IFN-γR-dependent mechanism regulates CD8+T suppressor cell recruitment, limits immunopathogenesis, preserves lung function, and enhances the resolution of PcP-related IRIS.
