M-CSF stimulated alveolar macrophages safeguard from invasive aspergillosis

Invasive pulmonary aspergillosis poses a life-threatening complication in immunocompromised individuals, including recipients of allogeneic hematopoietic cell transplantation (allo-HCT). By contrast, immunocompetent individuals are usually protected against infection with Aspergillus fumigatus, the causative agent of aspergillosis. The mechanisms underlying pulmonary innate immune protection remain poorly understood. Here, we identify alveolar macrophages (AMs) as key players in pulmonary antifungal defense. In immunocompromised mice, AMs conferred protection against lethal invasive aspergillosis by day 6, but not day 4 post-allo-HCT. To enhance AM function at the earlier time point, we tested cytokine-based interventions and showed that M-CSF, but not IL-34, which both bind to the CSF-1 receptor, promotes migratory activity, phagolysosomal function and fungal killing in both mouse and human primary tissue-resident AMs. In allo-HCT recipient mice, M-CSF treatment preserved lung tissue integrity, suppressed pro-inflammatory cytokines, and protected mice from lethal invasive aspergillosis. The M-CSF-driven protective effect was abrogated upon AM depletion. Our findings demonstrate a critical role of tissue-resident AMs in pulmonary antifungal immunity and suggest that therapeutic modulation of AM activity via M-CSF may offer a promising strategy to combat severe fungal infections in immunocompromised patients.