Cell-type-specific efferocytosis determines functional plasticity of alveolar macrophages
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PROVIDER: PRJNA1214782 | ENA |
REPOSITORIES: ENA
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Project description:Acid aspiration of gastric contents leads to aspiration pneumonitis, and as such predisposes to severe secondary bacterial infections. Alveolar macrophages are key sentinel cells in the lung, which initiate and resolve an inflammatory process. We found that after acid aspiration resident alveolar macrophages are impaired in their capacity to eliminate the clinically relevant bacterium Pseudomonas aeruginosa ex vivo and in vivo. Reduced bacterial killing peaked around 24 hours after the hit with acid, was detected up to 4 days later, and returned to normal 7 days after acid aspiration. We therefore want to characterize the capacity of avleolar macrophages after acid aspiration over time to respond to Pseudomonas aeruginosa. We expect a pro-resolving M2-like differentiation, which we aim to characterize in more detail: which inflammatory pathways are differentially regulated, are genes associated with bactericidal functions affected, is there a difference in the metabolic response.
2025-02-01 | GSE287821 | GEO
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.
2023-08-16 | GSE231217 | GEO
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.
2023-08-16 | GSE231218 | GEO
Project description:Inflammation is a physiopathological process triggered by infection or tissue damage. Immune system initiates coordinated sequential steps in response to these danger signals. Once the threat has been contained inflammation has to be subsequently shut down. Inflammation resolution is initiated by the reprogramming of pro-inflammatory macrophages toward a pro-resolving profile. This reprogramming is induced in particular by the non-phlogistic engulfment of apoptotic cells, mostly apoptotic neutrophils, a process called efferocytosis. As a matter of fact, macrophages are an essential linchpin regulating both inflammation triggering and sustaining and inflammation resolution. This duality can be achieved through the tremendous plasticity of these innate immune cells. Indeed, depending on microenvironmental signals (cytokines, efferocytosis, growth factors…) macrophages can adopt numerous diverse and sometimes antagonistic phenotypes. The mechanisms governing these transitions remain relatively scattered especially in human. With this project we propose to explore the mechanisms involved in human macrophage reprogramming toward a pro-resolving profile after efferocytosis. The stakes are high due to the estimated prevalence of chronic inflammatory diseases in Western society is 5 to 7%. Chronic inflammation is a burden to patient due to life-long debilitating illness and increased mortality and is also a burden to society due to high costs for therapy and care. Finding new therapies to limit chronic inflammation establishment and persistence is thus a highly valuable goal.
2021-12-01 | E-MTAB-8885 | biostudies-arrayexpress
Project description:Poor wound healing due to dysregulated tissue repair responses can exacerbate and prolong disease. Successful tissue repair is critically dependent on the timely clearance of apoptotic cells by macrophages in a process termed efferocytosis. Mechanisms and factors that link these two fundamental processes are therefore of great interest. Herein, we observed that a subset of 12-lipoxygenase (ALOX12)-expressing macrophages upregulate the production of host protective autacoids termed maresin conjugates in tissue regeneration (MCTR) during efferocytosis. MCTRs in turn play autocrine and paracrine functions in enhancing the ability of both ALOX12-positive and surrounding ALOX12-negative macrophages to uptake apoptotic cells. These effects of ALOX12-positive macrophages and MCTRs in regulating apoptotic cells clearance was also observed at sites of high apoptotic cell burden in mouse and flatworm models, as the formation of these mediators was upregulated and abrogation of related ALOX activity in mice reduced the ability of macrophages to clear apoptotic cells. Furthermore, add-back of MCTRs rapidly enhanced the efferocytosis capability of macrophages in mice and planarian flatworms. Mechanistic studies in macrophages revealed that MCTRs modulated Rac1 signalling and glycolytic metabolism, two pathways crucial for effective efferocytosis, and enhanced efferocytosis-induced WNT ligand production. Inhibition of Rac1 abrogated the ability of MCTRs to enhance glucose uptake and efferocytosis in vitro, while inhibiting either Rac1, glycolysis, or WNT ligand production prevented MCTR-mediated enhancement of apoptotic cell clearance and tissue regeneration. Taken together, our findings identify a central role for ALOX12-expressing macrophages in the regulation of efferocytosis and tissue repair via the local formation of MCTRs.
2023-12-12 | PXD038390 | Pride
Project description:Trained immunity of alveolar macrophages promotes injury resolution by enhancing KLF4-MERTK-mediated efferocytosis
| PRJNA963001 | ENA
Project description:Trained immunity of alveolar macrophages promotes injury resolution by enhancing KLF4-MERTK-mediated efferocytosis.
| PRJNA962998 | ENA
Project description:RationaleIdiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrosing interstitial pneumonia. The pathogenicity of IPF has been widely investigated but still remains to be clarified. Efferocytosis, the specialized recognition and ingestion of apoptotic cells by phagocytes, is essential for the resolution of inflammation in the lungs and repair of injured tissues. Impaired efferocytosis contributes to the pathogenesis of chronic lung diseases such as emphysema and cystic fibrosis. We hypothesized that efferocytosis would also be reduced in alveolar macrophages isolated from subjects with IPF.MethodsEfferocytosis, was evaluated using Wright-Giemsa stained cell preparations isolated from the bronchoalveolar lavage (BAL) fluid of patients with IPF (n = 5), nonspecific interstitial pneumonitis (n = 6), cryptogenic organizing pneumonia (n = 4) and eosinophilic pneumonia (EP) (n = 5).ResultsUningested apoptotic cells were significantly higher in BAL fluid from patients with IPF compared to other forms of interstitial lung disease. Macrophages isolated from patients with eosinophilic pneumonia had significantly fewer phagocytic ingestions than macrophages from the other three groups.ConclusionEfferocytosis by alveolar macrophages was significantly lower in subjects with IPF compared to subjects with other interstitial pneumonia. Dysregulated efferocytosis may contribute to the pathogenesis of IPF.
| S-EPMC4030720 | biostudies-literature
Project description:Within the human lung, interplay between alveolar epithelial cells and resident macrophages shape lung development and function in both health and disease. To study these processes, we devised a strategy for co-culturing hPSC-derived alveolar epithelial organoids and induced macrophages to form functional environment, which we name alveolar assembloids (AlvAssemb). By scRNAseq and functional analysis of AlvAssemb, we identified alveolar type 2-like cells that produced GM-CSF, a response associated with tissue adaptation of macrophages, and that resident alveolar macrophage-like cells secreted interleukin-1β and interleukin-6, a core immune response function, and expressed genes required for surfactant metabolism. Remarkably, in response to alveolar epithelial injury, we found that macrophage-like cells within AlvAssemb efficiently eliminated damaged cells and absorbed oxidized lipids. Moreover, in response to lipopolysaccharide exposure and Mycobacterium tuberculosis infection, we found that core features of the human respiratory defense response were replicated in AlvAssemb. These findings support that AlvAssemb could serve as a valuable platform to investigate human lung development and pathology.
2024-09-30 | GSE269733 | GEO
Project description:Generation of Alveolar Assembloids (AlvAssemb) with Functional Alveolar-like Macrophages
| PRJNA1123576 | ENA