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 trained immunity by reprogramming hematopoietic stem cells (HSCs) in the bone marrow generating trained innate cells with enhanced responsiveness. In the present study, we show that systemic administration of β-glucan reprograms alveolar macrophages (AMs) in the lung via neutrophils and IFNγ signalling, 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. 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.