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

Reviewer #1 (Public review):

Summary:

The concept that trained immunity, as defined, can be beneficial to subsequent immune challenges is important in the broad context of health and disease. The significance of this manuscript is the finding that trained immunity is actually a two-edged sword, herein, detrimental in the context of LPS-induced Acute Lung Injury that is mediated by AMs.

Strengths:

Several lines of evidence in different mouse models support this conclusion. The postulation that differences in immune responses in individuals are linked to differences in the mycobiome and consequent B-glucan makeup is provocative.

Weaknesses:

The findings that the authors state are relevant to sepsis, are actually confined to a specific lung injury model and not classically-defined sepsis. In addition, the ontogeny of the reprogrammed AMs is uncertain. Links in the proposed signaling pathways need to be strengthened.

Reviewer #2 (Public review):

Summary:

Prével et al. present an in vivo study in which they reveal an interesting aspect of β-glucan, a known inducer of enhanced immune responses termed trained immunity in sterile inflammation. The authors can show, that β-glucan's can reprogram alveolar macrophages (AMs) in the lungs through neutrophils and IFNγ signaling and independent of Dectin1. This reprogramming occurs at both transcriptional and metabolic levels. After β-glucan training, LPS-induced sterile inflammation exacerbated acute lung injury via enhanced immunopathology. These findings highlight a new aspect of β-glucan's role in trained immunity and its potential detrimental effects when enhanced pathogen clearance is not required.

Strengths:

(1) This manuscript is well-written and effectively conveys its message.

(2) The authors provide important evidence that β-glucan training is not solely beneficial, but depending on the context can also enhance immunopathology. This will be important to the field for two reasons. It shows again, that trained immunity can also be harmful. Jentho et al. 2021 have already provided further evidence for this aspect. And it highlights anew that LPS application is an insufficient infection model.

Weaknesses:

(1) Only a little physiological data is provided by the in vivo models.

(2) The effects in histology appear to be rather weak.