Key Points

Monocytes have impaired antifungal effector function in neutropenic mice.

STAT1 expression on CCR2+ monocytes is required for defense against IA.

Neutrophils are a relevant direct source of IFN-γ during aspergillosis.

Visual AbstractAbstract

Neutrophils are critical for the direct eradication of Aspergillus fumigatus conidia, but whether they mediate antifungal defense beyond their role as effectors is unclear. In this study, we demonstrate that neutrophil depletion impairs the activation of protective antifungal CCR2+ inflammatory monocytes. In the absence of neutrophils, monocytes displayed limited differentiation into monocyte-derived dendritic cells, reduced formation of reactive oxygen species, and diminished conidiacidal activity. Upstream regulator analysis of the transcriptional response in monocytes predicted a loss of STAT1-dependent signals as the potential basis for the dysfunction seen in neutrophil-depleted mice. We find that conditional removal of STAT1 on CCR2+ cells results in diminished antifungal monocyte responses, whereas exogenous administration of IFN-γ to neutrophil-depleted mice restores monocyte-derived dendritic cell maturation and reactive oxygen species production. Altogether, our findings support a critical role for neutrophils in antifungal immunity not only as effectors but also as important contributors to antifungal monocyte activation, in part by regulating STAT1-dependent functions.

Footnotes

This work was supported by the National Institute of Allergy and Infectious Diseases Grants R01AI114647-01A1 (to A.R.), R01AI169769 (to A.R.), R01AI123224 (to M.C.S.), R01AI131634 (to M.C.S.), R37AI093808 (to T.M.H.), R01AI13932 (to T.M.H.), K08AI130366 (to L.J.H.), and R01AI162765 (to L.J.H.). A.R. and T.M.H. were supported by Investigator in the Pathogenesis of Infectious Disease Awards from the Burroughs Wellcome Fund. The content is solely the responsibility of the authors and does not represent the official views of the National Institutes of Health or Burroughs Wellcome Fund.

The online version of this article contains supplemental material.

Abbreviations used in this article:

BALbronchoalveolar lavageCCR2+MoCCR2+ inflammatory monocyteFLAREfluorescent Aspergillus reporterIAinvasive aspergillosisMHC IIMHC class IIMo-DCmonocyte-derived dendritic cellRNA-seqRNA sequencingROSreactive oxygen speciesReceived June 23, 2022.Accepted September 20, 2022.Copyright © 2022 by The American Association of Immunologists, Inc.