Study of human macrophage reprogramming toward a pro-resolving profile by efferocytosis
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ABSTRACT:
PROVIDER: PRJEB37205 | ENA |
REPOSITORIES: ENA
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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:Specialized Pro-resolving Mediators Regulate Treg Differentiation
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Project description:We aim to demonstrate a central role for omega-3 derived autacoids, termed specialized pro-resolving mediators (SPM), in the differentiation and maturation of Tregs.
2021-06-10 | GSE140750 | GEO
Project description:Regression of atherosclerosis is an important clinical goal, however the pathways that mediate the resolution of atherosclerotic inflammation and reversal of plaques are poorly understood. Regulatory T cells (Tregs) have been shown to be atheroprotective, however numbers of these immunosuppressive cells decrease with disease progression. Using multiple independent mouse models of atherosclerosis regression, we demonstrate that an increase in plaque Tregs is a common signature of regressing plaques. To test if Tregs are required for the resolution of atherosclerotic inflammation and plaque regression during lipid-lowering therapy, we combined CD25 monoclonal antibody (PC61 mAb)-mediated Treg depletion with single-cell RNA-sequencing of immune cells in the plaque and conventional analyses of atherosclerosis. Single cell RNA-sequencing revealed that Tregs from aortic plaques shared some similarity with splenic Tregs, but were distinct from skin and colon Tregs supporting recent findings of tissue-dependent Treg heterogeneity. Furthermore, Tregs from progressing plaques expressed markers of natural Tregs derived from the thymus, whereas Tregs in regressing plaques lacked Nrp1 and Helios expression, suggesting that they are induced in the periphery during lipid lowering. Treatment of atherosclerotic mice with PC61 mAb effectively depleted Tregs in the blood and peripheral tissues, including plaques, and blocked the regression of atherosclerosis induced by apoB anti-sense oligonucleotides. Morphometric analyses revealed that control antibody-treated mice showed a 40% decrease in plaque burden and macrophage content under regression conditions, whereas PC61 mAb-treated mice showed no change in plaque size or inflammatory cell content compared to baseline. Moreover, Treg depletion enhanced inflammatory signaling and blocked tissue reparative functions of macrophages in the regressing plaque, including M2-polarization, efferocytosis and sensing of specialized pro-resolving lipid mediators. Together, these data establish essential roles for Tregs in the resolution of atherosclerotic inflammation and plaque remodeling during regression.
2020-07-22 | GSE141038 | GEO
Project description:Regulatory T cells license macrophage pro-resolving functions in atherosclerosis regression
| PRJNA591821 | ENA
Project description:Defects in apoptotic cell clearance, or efferocytosis, can cause inflammatory diseases and prevent tissue repair due in part, to a key role of efferocytosis in inducing a pro-repair transcriptional program in phagocytic cells like macrophages. While the cellular machinery and metabolic pathways involved in efferocytosis have been characterized, the precise efferocytic response of macrophages is dependent on the identity and macromolecular cues of apoptotic cells, and the complex tissue microenvironment in which efferocytosis occurs. Here, we find that macrophages undergoing active efferocytosis in mid-stage mouse skin wounds in vivo display a pro-repair gene program, while efferocytosis of apoptotic skin fibroblasts in vitro induces an immature/inflammatory transcription response. These data provide a resource for understanding how the skin wound niche influences macrophage efferocytosis and will be useful for future investigations that define the role of efferocytosis during tissue repair
2024-08-06 | GSE273754 | GEO
Project description:Phagocytes orchestrate acute inflammation and host defense. Here we carried out lipid mediator (LM) metabololipidomics profiling distinct phagocytes: neutrophils (PMN), apoptotic PMN, and macrophages. Efferocytosis increased specialized pro-resolving mediator (SPM) biosynthesis, including Resolvin D1 (RvD1), RvD2, and RvE2, which were further elevated by PMN microparticles. Apoptotic PMN gave elevated prostaglandin E(2), lipoxin B(4) and RvE2, whereas zymosan-stimulated PMN showed predominantly leukotriene B(4) and 20-OH-leukotriene B(4), as well as lipoxin marker 5,15-diHETE. Using deuterium-labeled precursors (d(8)-arachidonic acid, d(5)-eicosapentaenoic acid, and d(5)-docosahexaenoic acid), we found that apoptotic PMN and microparticles contributed to SPM biosynthesis during efferocytosis. M2 macrophages produced SPM including maresin-1 (299 ± 8 vs 45 ± 6 pg/2.5 × 10(5) cells; P < .01) and lower amounts of leukotriene B(4) and prostaglandin than M1. Apoptotic PMN uptake by both macrophage subtypes led to modulation of their LM profiles. Leukotriene B(4) was down-regulated in M2 (668 ± 81 vs 351 ± 39 pg/2.5 × 10(5) cells; P < .01), whereas SPM including lipoxin A(4) (977 ± 173 vs 675 ± 167 pg/2.5 × 10(5) cells; P < .05) were increased. Conversely, uptake of apoptotic PMN by M2 macrophages reduced (? 25%) overall LM. Together, these results establish LM signature profiles of human phagocytes and related subpopulations. Moreover, they provide evidence for microparticle regulation of specific endogenous LM during defined stages of the acute inflammatory process and their dynamic changes in human primary phagocytes.
| S-EPMC3471524 | biostudies-literature
Project description:Despite the importance of rapid adaptive responses for an efficient resolution of inflammation, which are commonly regulated on a post-transcriptional and specifically translational level, translational changes caused by efferocytosis remain largely elusive. To gain further insights into such gene regulatory principles, we analyzed translational changes in efferocytic and non-efferocytic bone marrow-derived macrophages (BMDM) in the course of inflammation. Using total RNA-sequencing, we confirmed that efferocytosis induced a pro-resolution signature in LPS-stimulated, inflammatory macropahges. Interestingly though, while LPS-induced transcriptional changes appeared rather small between efferocytic and non-efferocytic macrophages, we observed considerable differences on the level of de novo synthesized proteins. We further identified translationally regulated targets showing reduced translation upon inflammatory stimulation, which was buffered upon efferocytosis. Herein, pro-resolving matrix metallopeptidase 12 (Mmp12) emerged as a novel translationally regulated candidate, which was translationally repressed during early inflammation and increased during the resolution phase. Functionally, the translational repression of Mmp12 was linked to increased spontaneous two-dimensional migration. In summary, we identified the novel translationally regulated target Mmp12 in the context of the resolution of inflammation in primary murine macrophages, which is associated with a modulation of spontaneous migration.
2023-12-13 | GSE245834 | GEO
Project description:Damage-associated molecular patterns induce macrophage polarization toward an M1 pro-inflammatory phenotype
| PRJNA421349 | ENA
Project description:To facilitate the recovery process of chronic and hard-to-heal wounds novel pro-resolving treatment options are urgently needed. We investigated the pro regenerative properties of soluble CD83 (sCD83) on cutaneous wound healing, where sCD83 accelerated wound healing not only after systemic but also after topical application, which is of high therapeutic interest. Cytokine profile analyses revealed an initial upregulation of inflammatory mediators such as TNFa and IL-1b, followed by a switch towards pro-resolving factors, including YM-1 and IL-10, both expressed by tissue repair macrophages. These cells are known to mediate resolution of inflammation and stimulate wound healing processes by secretion of growth factors such as epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF), which promote vascularization as well as fibroblast and keratinocyte differentiation. In conclusion, we have found strong wound healing capacities of sCD83 beyond the previously described role in transplantation and autoimmunity. This makes sCD83 a promising candidate for the treatment of chronic- and hard-to-heal wounds
2022-09-30 | GSE214079 | GEO