Expression data from macrophages sorted from the heart tissue of WT mice post-IR
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE246339 | GEO | 2023/10/31
REPOSITORIES: GEO
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Project description:Cardiac resident MerTK+ macrophages exert multiple protective roles post-ischemic injury, however, the mechanisms regulating their fate are not fully understood. Here we show that GAS6-inducible transcription factor ATF3 prevents apoptosis of MerTK+ macrophages after ischemia-reperfusion (IR) injury, by repressing the transcription of multiple genes involved in type I interferon expression (Ifih1 and Infb1) and apoptosis (Apaf1). Mice lacking ATF3 in cardiac macrophages or myeloid cells showed excessive loss of MerTK+ cardiac macrophages, poor angiogenesis, and worse heart dysfunction post-IR, which were rescued by the transfer of MerTK+ cardiac macrophages. GAS6 administration improved cardiac repair in an ATF3-dependent manner. Finally, we showed a negative association of GAS6 and ATF3 expression with the risk of major adverse cardiac events in patients with ischemic heart disease. These results indicate that the GAS6-ATF3 axis has a protective role against IR injury by regulating MerTK+ cardiac macrophage survival/proliferation.
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Project description:Tissue-resident macrophages represent a group of highly responsive innate immune cells that acquire diverse functions by polarizing towards distinct subgroups. The subgroups of macrophages that reside in skeletal muscle (SKM) and their changes during aging are not fully understood. By single-cell transcriptomic analysis, we found that mouse SKM macrophages comprise two large populations, Lyve1+ and Lyve1-. Lyve1+ macrophages expressed high levels of mRNAs encoding angiogenesis and tissue repair proteins, while Lyve1- macrophages expressed high levels of mRNAs encoding proteins with functions in translation, antigen presentation, and the proinflammatory response. SKM macrophages were further classified into four functional subgroups based on the expression levels of another cell surface marker MHCII: Lyve1+/MHCII-lo (similar to alternatively activated M2), Lyve1-/MHCII-hi (similar to classically activated M1), and two new subgroups, Lyve1+/MHCII-hi and Lyve1-/MHCII-lo, all displayed strong phagocytic capacities. Flow cytometric analysis validated the presence of the four macrophage subgroups in SKM. The new subgroup Lyve1+/MHCII-hi had traits of both M2 and M1 macrophages, while the other subgroup, Lyve1-/MHCII-lo, expressed high levels of mRNAs encoding cytotoxicity proteins. In old SKM, Lyve1+/MHCII-hi macrophages were less abundant and Lyve1-/MHCII-hi macrophages were more abundant. Furthermore, complementary unsupervised classification revealed the emergence of small clusters expressing proinflammatory markers including S100a8 and S100a9 mRNAs in aged SKM. In sum, our study has identified dynamically polarized mouse SKM macrophages and a shift toward a proinflammatory status during aging.
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Project description:In our study, we detected activation of ACKR3 signaling in cardiac lymphatics adjacent to the site of ischemic injury of left anterior descending artery (LAD) ligation. Furthermore, we found that Ackr3∆Lyve1 mice exhibited better survival and were protected from the formation of acute tissue edema after ischemic cardiac injury, in addition to a denser cardiac lymphatic network after LAD ligation, especially in the injured tissues. To characterize the transcriptomic changes in cardiac lymphatic endothelial cell (LEC) and macrophage populations in the heart upon ischemic cardiac injury in Ackr3∆Lyve1 mice, CD68+ macrophages and CD68-/LYVE1+ LECs were immunoprecipitated from the ventricles of Ackr3fl/fl and Ackr3∆Lyve1 mice at baseline or 7 days post LAD ligation. We then performed microarray on the collected lymphatic and macrophage RNA samples.
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Project description:To determine the mechanism by which ATF3 regulated the survival/proliferation of MerTK+ cardiac macrophages, microarray was performed to identify gene expression differences in MerTK+ macrophages from WT and ATF3-CKO mice under the HR state.
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2025-03-04 | GSE210549 | GEO
Project description:Streptococcus pneumoniae is the leading cause of community-acquired pneumonia. Mertk is an efferocytosis receptor involved in the recognition and removal of apoptotic debris by macrophages and other phagocytic cells. Here we show that Mertk negatively regulates the clearance of S. pneumoniae, as measured by the greater number of viable bacteria in the lung of wild type vs. Mertk-/- mice 24 hours post-inoculation. The impaired clearance observed in wild type mice was associated with a greater number of neutrophils in the bronchoalveolar lavage (BAL) and lower concentration of IFNγ in the BAL fluid; however, similar enhancement of clearance was observed in Mertk-/- mice receiving neutralizing IFNγ antibody. Mertk is highly expressed on alveolar macrophages. Transcriptomic changes observed in primary Mertk-/- alveolar macrophages were associated with leukocyte activation, cellular motility, and response to stimulus. Mertk deficiency similarly enhanced proinflammatory gene expression in S. pneumoniae-stimulated alveolar macrophages in vitro and in pneumonic lung tissue. Thus, Mertk contributes to alveolar macrophage homeostasis through the receptor’s immunomodulatory role. Naive Mertk-/- alveolar macrophages appear primed for an inflammatory response to S. pneumoniae leading to greater cell motility, improved bacterial killing and enhancement of other innate immune cells through the production of inflammatory mediators.
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Project description:Streptococcus pneumoniae is the leading cause of community-acquired pneumonia. Mertk is an efferocytosis receptor involved in the recognition and removal of apoptotic debris by macrophages and other phagocytic cells. Here we show that Mertk negatively regulates the clearance of S. pneumoniae, as measured by the greater number of viable bacteria in the lung of wild type vs. Mertk-/- mice 24 hours post-inoculation. The impaired clearance observed in wild type mice was associated with a greater number of neutrophils in the bronchoalveolar lavage (BAL) and lower concentration of IFNγ in the BAL fluid; however, similar enhancement of clearance was observed in Mertk-/- mice receiving neutralizing IFNγ antibody. Mertk is highly expressed on alveolar macrophages. Transcriptomic changes observed in primary Mertk-/- alveolar macrophages were associated with leukocyte activation, cellular motility, and response to stimulus. Mertk deficiency similarly enhanced proinflammatory gene expression in S. pneumoniae-stimulated alveolar macrophages in vitro and in pneumonic lung tissue. Thus, Mertk contributes to alveolar macrophage homeostasis through the receptor’s immunomodulatory role. Naive Mertk-/- alveolar macrophages appear primed for an inflammatory response to S. pneumoniae leading to greater cell motility, improved bacterial killing and enhancement of other innate immune cells through the production of inflammatory mediators.
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Project description:Recent reports have suggested a protective role for vascular endothelial growth factor C (VEGFC) during acute cardiac lymphangiogenesis post MI. Glinton et al. report that defective efferocytosis by macrophages after experimental MI leads to a reduction in cardiac lymphangiogenesis and Vegfc expression.
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