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.
Highlights
The incidence of fungal infections has been on the rise for several decades due to increased use of immunosuppressive and myeloablative therapies for malignant and non-malignant diseases [1,2,3]
Our studies indicate that chemokine receptor-2 (CCR2)+Mo and monocytederived dendritic cells (Mo-DCs) exert crucial innate antifungal defense by two main mechanisms: 1) CCR2+CD11b+Ly6C+ inflammatory monocytes (CCR2+Mo) and Mo-DCs are a significant source of inflammatory mediators that augment the killing capacity of neutrophils and 2) conidial uptake by CCR2+Mo is coincident with their differentiation into Mo-DCs that directly kill fungal conidia via partially NADPH oxidasedependent mechanisms
CCR2+ inflammatory monocyte-depleted mice develop invasive aspergillosis To examine the contributions of CCR2+ Mo and their derivatives to respiratory fungal defense, we monitored the outcome of intratracheal A. fumigatus conidial challenge in CCR2 depleter mice [38] that express a functional diphtheria toxin receptor (DTR) under control of the CCR2 promoter
Summary
The incidence of fungal infections has been on the rise for several decades due to increased use of immunosuppressive and myeloablative therapies for malignant and non-malignant diseases [1,2,3]. Human susceptibility to IA in patients with defective neutrophil function (e.g. patients with chronic granulomatous disease) underscores the functional role of neutrophils in host defense. These findings are recapitulated in animal models of IA in which antibody-mediated depletion of neutrophils leads to uncontrolled fungal growth in the lung and to mortality from IA [19,20,21,22,23]. Despite the important contributions of other innate cells subsets in antifungal immunity, previous studies suggest that neutrophils are the sole indispensable innate effector cell in host defense against IA [19,20,21,22]
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