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

ABSTRACT: Environmental microbial triggers shape the development and functionality of the immune system. Alveolar macrophages (AMs), tissue-resident macrophages of the lungs, are in constant and direct contact with inhaled particles and microbes. Such exposures likely impact AM reactivity to subsequent challenges by immunological imprinting mechanisms referred to as trained immunity. Here, we investigated whether a ubiquitous microbial compound has the potential to induce AM training in vivo. We showed that intranasal exposure to ambient amounts of lipopolysaccharide (LPS) protected mice from bacterial pneumonia six days later and discovered a pronounced AM memory response, characterized by enhanced reactivity upon pneumococcal challenge. Exploring the mechanistic basis of AM training, we identified a critical role of type 1 interferon signaling and found that trained AMs displayed a substantially modulated metabolite and lipid composition. Inhibition of fatty acid oxidation and glutaminolysis significantly attenuated the training effect, suggesting a key function of metabolic rewiring in LPS-induced AM memory. Collectively, our findings demonstrate the profound impact of ambient microbial exposure on pulmonary immune memory and highlight tissue-specific features of trained immunity.

ORGANISM(S): Mus musculus

PROVIDER: GSE184683 | GEO | 2022/07/18

REPOSITORIES: GEO

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

Project description:Environmental microbial triggers shape the development and functionality of the immune system. Alveolar macrophages (AMs), tissue-resident macrophages of the lungs, are in constant and direct contact with inhaled particles and microbes. Such exposures likely impact AM reactivity to subsequent challenges by immunological imprinting mechanisms referred to as trained immunity. Here, we investigated whether a ubiquitous microbial compound has the potential to induce AM training in vivo. We showed that intranasal exposure to ambient amounts of lipopolysaccharide (LPS) protected mice from bacterial pneumonia six days later and discovered a pronounced AM memory response, characterized by enhanced reactivity upon pneumococcal challenge. Exploring the mechanistic basis of AM training, we identified a critical role of type 1 interferon signaling and found that trained AMs displayed a substantially modulated metabolite and lipid composition. Inhibition of fatty acid oxidation and glutaminolysis significantly attenuated the training effect, suggesting a key function of metabolic rewiring in LPS-induced AM memory. Collectively, our findings demonstrate the profound impact of ambient microbial exposure on pulmonary immune memory and highlight tissue-specific features of trained immunity.

2022-07-18 | GSE184682 | GEO

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 promotes injury resolution by enhancing KLF4-MERTK-mediated efferocytosis

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Influenza-trained mucosal-resident alveolar macrophages confer long-term antitumor immunity in the lungs [ATAC-seq]

Project description:Respiratory viral infections reprogram pulmonary macrophages with altered anti-infectious functions. However, the potential function of virus-trained macrophages in antitumor immunity in the lung, a preferential target of both primary and metastatic malignancies, is not well understood. Using mouse models of influenza and lung metastatic tumors, we show here that influenza trains respiratory mucosal-resident alveolar macrophages (AMs) to exert long-lasting and tissue-specific antitumor immunity. Trained AMs infiltrate tumor lesions and have enhanced phagocytic and tumor cell cytotoxic functions, which are associated with epigenetic, transcriptional and metabolic resistance to tumor-induced immune suppression. Generation of antitumor trained immunity in AMs is dependent on interferon-γ and natural killer cells. Notably, human AMs with trained immunity traits in non-small cell lung cancer tissue are associated with a favorable immune microenvironment. These data reveal a function for trained resident macrophages in pulmonary mucosal antitumor immune surveillance. Induction of trained immunity in tissue-resident macrophages might thereby be a potential antitumor strategy.

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Influenza-trained mucosal-resident alveolar macrophages confer long-term antitumor immunity in the lungs [RNA-seq]

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Project description:Trained innate immunity has been shown for human macrophages, i.e. a primary stimulation with specific compounds such as Beta-glucans, BCG vaccine or oxidized LDL generates an innate memory capacity that leads to an amplified pro-inflammatory reaction to various microbial components when restimulated days later. In this study, phorbol ester differentiated THP-1 cells were used as a model for human macrophages. The aim of this experiment was to map the biological processes involved in DCATH-2 peptide trained THP-1 cells versus control cells without restimulation and after restimulation with lipopolysaccharides.

2022-04-19 | E-MTAB-11601 | biostudies-arrayexpress

Epigenomes and Transcriptomes of human monocytes from Hyper IgD Syndrome (HIDS) patients

Project description:Innate immune memory, also refered to as trained immunity (TRIM) is the phenomenon whereby innate immune cells such as monocytes or macrophages undergo functional reprogramming after exposure to microbial components. In this study we performed epigenomic and transcriptomic analysis of HIDS (Hyper IgD Syndrome) patients at baseline, and after 24 hours culture in media (RPMI only) or media + 10ng/mL LPS. HIDS is associated with the accumulation of mevalonate, a monocyte trainer.

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2017-12-08 | GSE107821 | GEO

Transcriptional remodeling of primary human monocytes exposed to itaconate and its derivatives in the context of trained immunity

Project description:Trained immunity is a phenomenon whereby innate immune cells such as monocytes or macrophages undergo functional reprogramming after exposure to certain microbial components, altering their responses to future exposures. This study profiled the transcriptome of human monocytes and in vitro differentiated macrophages, exposed to a combination of LPS, BG, DMI, or Itaconate.

2023-06-26 | GSE212282 | GEO

Epigenome maps of time-resolved monocyte to macrophage differentiation and innate immune memory (ChIP-Seq)

Project description:Innate immune memory is the phenomenon whereby innate immune cells such as monocytes or macrophages undergo functional reprogramming after exposure to microbial components such as LPS. We apply an integrated epigenomic approach to characterize the molecular events involved in LPS-induced tolerance in a time dependent manner. ChIP-seq, RNA-seq, WGBS and ATAC-seq data were generated. This analysis identified epigenetic programs in tolerance and trained macrophages, and the potential transcription factors involved.

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