Inflammatory Monocytes Orchestrate Innate Antifungal Immunity in the Lung

PLoS Pathogens

Orchi Dutta¹  Peicheng Du¹  Yacov Ron²  Anupam Jhingran³  Robert Donnelly³  Vanessa Espinosa⁴  Shinji Kasahara⁴  Jeffrey Rosenfeld⁵  Ingrid Leiner⁵  Chiann-Chyi Chen⁵  Amariliz Rivera⁶  Tobias M. Hohl⁶ 

[1] Fred Hutchinson Cancer Research Center, Vaccine and Infectious Disease Division, Seattle, Washington, United States of America;Memorial Sloan Kettering Cancer Center, Sloan Kettering Institute, New York, New York, United States of America;Rutgers, Graduate School of Biomedical Sciences, Newark, New Jersey, United States of America;Rutgers, New Jersey Medical School, Department of Pediatrics, Center for Immunity and Inflammation, Newark, New Jersey, United States of America;Rutgers, New Jersey Medical School, Molecular Resource Facility and High Performance and Research Computing Group, Office of Information Technology, Rutgers University, Newark, New Jersey, United States of America;Rutgers, Robert Wood Johnson Medical School, Department of Pharmacology, Piscataway, New Jersey, United States of America

关键词: Neutrophils;    Respiratory infections;    Monocytes;    Fungal diseases;    Antifungals;    Inflammation;    NK cells;    Aspergillus fumigatus;   

DOI  :  10.1371/journal.ppat.1003940

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Aspergillus fumigatus is an environmental fungus that causes invasive aspergillosis (IA) in immunocompromised patients. Although -CC-chemokine receptor-2 (CCR2) and Ly6C-expressing inflammatory monocytes (CCR2+Mo) and their derivatives initiate adaptive pulmonary immune responses, their role in coordinating innate immune responses in the lung remain poorly defined. Using conditional and antibody-mediated cell ablation strategies, we found that CCR2+Mo and monocyte-derived dendritic cells (Mo-DCs) are essential for innate defense against inhaled conidia. By harnessing fluorescent Aspergillus reporter (FLARE) conidia that report fungal cell association and viability in vivo, we identify two mechanisms by which CCR2+Mo and Mo-DCs exert innate antifungal activity. First, CCR2+Mo and Mo-DCs condition the lung inflammatory milieu to augment neutrophil conidiacidal activity. Second, conidial uptake by CCR2+Mo temporally coincided with their differentiation into Mo-DCs, a process that resulted in direct conidial killing. Our findings illustrate both indirect and direct functions for CCR2+Mo and their derivatives in innate antifungal immunity in the lung.

【 授权许可】

CC BY