β-glucan reprograms alveolar macrophages via neutrophil/IFNγ axis to promote lung injury

Alveolar macrophages (AMs) reside in the lower airways and play a crucial role in lung health and response to sterile inflammation and infections. AMs possess remarkable adaptability to different environmental challenges that can persist through their memory capacity (trained immunity). β-glucan has been characterized as a potent inducer of central trained immunity by reprogramming hematopoietic stem cells (HSCs) in the bone marrow. In the present study, we show that systemic administration of β-glucan induces peripheral trained immunity by reprogramming alveolar macrophages (AMs) in the lungs, in a Dectin1-independent manner. We furthermore demonstrate that AM reprogramming at both the transcriptional and metabolic levels exacerbate lung injury following bacterial (LPS) or viral (polyI:C) challenges via a neutrophil/IFN-γ dependent manner. These findings identify an additional facet of β-glucan in trained immunity involving AM reprogramming and shed light on the potential detrimental effects of trained immunity.