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Trained immunity of alveolar macrophages promotes injury resolution by enhancing KLF4-MERTK-mediated efferocytosis

ABSTRACT: Recent studies suggest that training of innate immune cells such as tissue-resident macrophages by repeated noxious stimuli can heighten host defense responses. However, it remains unclear whether trained immunity of tissue-resident macrophages also comprises enhanced injury resolution capacity to counterbalance the heightened inflammatory responses. Here, we studied lung-resident alveolar macrophages (AMs) pre-challenged with either the bacterial endotoxin or with Pseudomonas aeruginosa and observed that these trained AMs showed greater resilience to pathogen-induced cell death. Transcriptomic analysis, and functional assays showed greater capacity of trained AMs to efferocytosis of cellular- debris, and facilitate injury resolution. Single-cell high-dimensional mass-cytometry analysis and lineage tracing demonstrated that training induces an expansion of a MERTKhiMarcohiCD163+F4/80low lung-resident AMs subset with pro-resolving phenotypes. Training epigenetically reprogrammed AMs to express a higher level of the transcription factor KLF4 which in turn upregulates the efferocytosis receptor MERTK. Adoptive transfer of these trained AMs restricted inflammatory lung injury in recipient mice exposed to lethal Pseudomonas aeruginosa. Thus, our study has identified a unique subset of tissue-resident trained macrophages which prevent hyper-inflammation and restore tissue homeostasis following pathogen challenge.

ORGANISM(S): Mus musculus

PROVIDER: GSE231217 | GEO | 2023/08/16

REPOSITORIES: GEO

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Trained immunity of alveolar macrophages promotes injury resolution by enhancing KLF4-MERTK-mediated efferocytosis [RNA-seq]

Project description:Recent studies suggest that training of innate immune cells such as tissue-resident macrophages by repeated noxious stimuli can heighten host defense responses. However, it remains unclear whether trained immunity of tissue-resident macrophages also comprises enhanced injury resolution capacity to counterbalance the heightened inflammatory responses. Here, we studied lung-resident alveolar macrophages (AMs) pre-challenged with either the bacterial endotoxin or with Pseudomonas aeruginosa and observed that these trained AMs showed greater resilience to pathogen-induced cell death. Transcriptomic analysis, and functional assays showed greater capacity of trained AMs to efferocytosis of cellular- debris, and facilitate injury resolution. Single-cell high-dimensional mass-cytometry analysis and lineage tracing demonstrated that training induces an expansion of a MERTKhiMarcohiCD163+F4/80low lung-resident AMs subset with pro-resolving phenotypes. Training epigenetically reprogrammed AMs to express a higher level of the transcription factor KLF4 which in turn upregulates the efferocytosis receptor MERTK. Adoptive transfer of these trained AMs restricted inflammatory lung injury in recipient mice exposed to lethal Pseudomonas aeruginosa. Thus, our study has identified a unique subset of tissue-resident trained macrophages which prevent hyper-inflammation and restore tissue homeostasis following pathogen challenge.

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Trained immunity of alveolar macrophages depends on metabolic rewiring and type 1 interferon signaling (ATAC-Seq)

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