title: Inflammatory monocytes orchestrate innate antifungal immunity in the lung.
abstract: 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.
authors.affiliation: Rutgers, New Jersey Medical School, Department of Pediatrics, Center for Immunity and Inflammation, Newark, New Jersey, United States of America ; Rutgers, Graduate School of Biomedical Sciences, Newark, New Jersey, United States of America.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Espinosa
authors.affiliation: Fred Hutchinson Cancer Research Center, Vaccine and Infectious Disease Division, Seattle, Washington, United States of America.
authors.forename: Anupam
authors.initials: A
authors.lastname: Jhingran
authors.affiliation: Rutgers, New Jersey Medical School, Department of Pediatrics, Center for Immunity and Inflammation, Newark, New Jersey, United States of America ; Rutgers, Graduate School of Biomedical Sciences, Newark, New Jersey, United States of America.
authors.forename: Orchi
authors.initials: O
authors.lastname: Dutta
authors.affiliation: Fred Hutchinson Cancer Research Center, Vaccine and Infectious Disease Division, Seattle, Washington, United States of America.
authors.forename: Shinji
authors.initials: S
authors.lastname: Kasahara
authors.affiliation: 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.
authors.forename: Robert
authors.initials: R
authors.lastname: Donnelly
authors.affiliation: 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.
authors.forename: Peicheng
authors.initials: P
authors.lastname: Du
authors.affiliation: 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.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Rosenfeld
authors.affiliation: Memorial Sloan Kettering Cancer Center, Sloan Kettering Institute, New York, New York, United States of America.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Leiner
authors.affiliation: Rutgers, Robert Wood Johnson Medical School, Department of Pharmacology, Piscataway, New Jersey, United States of America.
authors.forename: Chiann-Chyi
authors.initials: CC
authors.lastname: Chen
authors.affiliation: Rutgers, Robert Wood Johnson Medical School, Department of Pharmacology, Piscataway, New Jersey, United States of America.
authors.forename: Yacov
authors.initials: Y
authors.lastname: Ron
authors.affiliation: Fred Hutchinson Cancer Research Center, Vaccine and Infectious Disease Division, Seattle, Washington, United States of America.
authors.forename: Tobias M
authors.initials: TM
authors.lastname: Hohl
authors.affiliation: Rutgers, New Jersey Medical School, Department of Pediatrics, Center for Immunity and Inflammation, Newark, New Jersey, United States of America.
authors.forename: Amariliz
authors.initials: A
authors.lastname: Rivera
mesh_terms: D000818:Animals; D001232:Aspergillus fumigatus / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D007113:Immunity, Innate / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D055732:Pulmonary Aspergillosis / Q000276:immunology*; D060888:Real-Time Polymerase Chain Reaction; D054390:Receptors, CCR2 / Q000378:metabolism; D013172:Spores, Fungal / Q000276:immunology
chemical_list: C515335:Ccr2 protein, mouse; D054390:Receptors, CCR2