Neutrophils Restrain CCR2-Dependent Monocyte Immunopathology During Pulmonary Cryptococcosis

Neutrophils are essential for host defense against most invasive fungal pathogens, yet their role in cryptococcosis remains paradoxical. Neutropenia is not a recognized risk factor for cryptococcal disease, and an early study reported that neutrophil depletion improves survival in mice, supporting the prevailing view that these cells are dispensable. Here we re-examined this question using Ly6G-specific depletion strategies. Contrary to prior reports, neutrophil-depleted mice infected with Cryptococcus neoformans succumbed significantly more rapidly than isotype-treated controls. Accelerated mortality occurred without any increase in pulmonary fungal burden at 24h, 48h, or day 7, or in brain and spleen at day 7, indicating host-mediated rather than pathogen-driven death. This phenotype was independent of mouse genetic background, depletion antibody, inoculum, and fungal strain. Within 24h, neutrophil depletion provoked an early chemokine and IL-17A response, followed by pronounced pulmonary accumulation of inflammatory monocytes and macrophages by day 7. Strikingly, the increased mortality associated with neutrophil depletion was completely absent in Ccr2 ^-/- mice, implicating CCR2-dependent inflammatory responses in disease severity. Together, these findings reveal a previously underappreciated protective function of neutrophils during cryptococcosis, whereby they constrain inflammatory monocyte-associated immunopathology and promote host survival independently of measurable changes in fungal burden.