Introduction: Acute respiratory distress syndrome is responsible for 400,000 deaths per year worldwide. Despite five decades of research, no immunomodulatory treatment has been proven to be effective. Trained immunity (TI) is the ability for the innate immune system to be reprogrammed by a first insult, without persistent inflammation, then providing an increased response to a second insult. The aim of this study is to confirm that TI could protect from acute lung injury (ALI).

Methods: twelve weeks old C57BL/6J mice were intra-nasally instilled with 50?g and 100?g of LPS and with 50?g of poly(I:C), seven or thirty days after intra-peritoneal injection of a training agent (1mg of ?-1,3-(D)-glucan). Alveolar macrophages (AM) depletion was obtained by intra-nasal clodronate instillation. AM adoptive transfer was performed in Csf2rb-/- pups. ALI was assessed by lung imaging, histology, alveolar-capillary permeability, pro-inflammatory cytokines production and inflammatory cells recruitment. AM reprogramming was assessed ex vivo by pro-inflammatory cytokines production, metabolism exploration and transcriptomics.

Results: Lung injury is significantly increased in ?-glucan trained mice compared to controls in LPS and poly(I:C) models with long-term persistence. Depletion of AM alleviates this increase in ALI which is restored after adoptive transfer of trained AM, demonstrating the direct role of AM in increased inflammatory responses. AM reprogramming was confirmed ex vivo with increased pro-inflammatory cytokines production after LPS stimulation and switch to glycolytic metabolism.

Conclusion: ?-glucan reprograms alveolar macrophages promoting acute lung injury after LPS challenge.