Early Age Efferocytosis Directs Macrophage Arachidonic Acid Metabolism for Tissue Regeneration
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PROVIDER: PRJNA1010769 | ENA |
REPOSITORIES: ENA
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Project description:In response to organ injury in adults, macrophages often promote scarring, yet during early life are required for tissue regeneration. To elucidate mechanisms underlying age-associated regeneration, we compared the macrophage injury response in newborns versus adult hearts. Single cell analysis revealed an accumulation of tissue-resident macrophages in neonates that were selectively polarized for apoptotic cell recognition and uptake (efferocytosis). Ablation of the apoptotic cell recognition receptor Mertk in newborns prevented cardiac regeneration. These findings could be attributed to reprogramming of macrophage gene expression that was required for biosynthesis of the eicosanoid Thromboxane A2, which unexpectedly activated parenchymal cell proliferation. Markers of Thromboxane A2 production were suppressed in adult macrophages after efferocytosis. Moreover, macrophage-neighboring neonatal cardiomyocytes expressed the Thromboxane A2 receptor, whose activation induced a metabolic shift supporting cellular proliferation. Our data reveal a fundamental age-defined macrophage response in which lipid mitogens produced during efferocytosis support receptor-mediated tissue regeneration.
2024-12-11 | GSE241928 | 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:We identify arachidonic acid (AA), as a direct proliferation promoter of intestinal epithelial cells, facilitating small intestinal regeneration. In the transcriptomes, it shows that AA treatment upregulated proliferation-related genes including Wnt signaling target genes, while downregulated differentiation-related genes including enterocyte, goblet cell, Paneth cell, enteroendocrine cell, and tuft cell markers. Additionally, AA could also upregulate stem cell-associated genes which have been highly expressed three days after 12Gy IR injury (e.g. Clu, Lamc2, Anxa1, Areg, and Ly6d). The study shows that AA treatment can be considered a potential therapy for irradiation injury repair and tissue regeneration.
2020-07-27 | GSE146871 | GEO
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:Arachidonic acid promotes intestinal regeneration by activating Wnt signaling
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Project description:Efficient clearance and degradation of apoptotic cardiomyocytes by macrophages (termed efferocytosis) are critical for inflammation resolution and restoration of cardiac function after myocardial ischemia/reperfusion (I/R). Here, we define secreted and transmembrane protein 1a (Sectm1a), a cardiac macrophage-enriched gene, as a modulator of macrophage efferocytosis in I/R hearts. Upon myocardial I/R, Sectm1a-KO mice exhibit impaired macrophage efferocytosis, leading to massive accumulation of apoptotic cardiomyocytes, cardiac inflammation, fibrosis, and consequently, exaggerated cardiac dysfunction. By contrast, therapeutic administration of recombinant SECTM1A protein significantly enhances macrophage efferocytosis and improves cardiac function. Mechanistically, SECTM1A can elicit autocrine effects on the activation of glucocorticoid-induced TNF receptor (GITR) at the surface of macrophages, leading to the upregulation of liver X receptor alpha (LXRα) and its downstream efferocytosis-related genes and lysosomal enzyme genes. Our study suggests that Sectm1a-mediated activation of Gitr/LXRα axis could be a promising approach to enhance macrophage efferocytosis for the treatment of myocardial I/R injury.
2024-01-23 | GSE253579 | GEO
Project description:Single cell transcriptomic profiling (sc RNA-seq) of arachidonic acid (AA) induced gene expression pogram associated with regeneration in intestinal organoids.
2023-03-01 | GSE210728 | GEO
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Project description:Severe carbon monoxide (CO) poisoning can cause structural damage to the nervous system, leading to long-term cognitive dysfunction in patients. Correctly terminating the inflammatory response caused by neuronal damage is a prerequisite for tissue repair. Macrophages can clear the cell corpses/fragments caused by brain injury through efferocytosis, and produce cytokines to coordinate the immune response, promoting neuronal repair and regeneration. However, in the microenvironment of the nervous system affected by CO poisoning, the function of macrophages is inhibited. Our research found that CLCF1 can regulate the secretion of cytokines such as TNF-α, IL-1β, and IL-10 through the NF-κB signaling pathway, thereby affecting neural cell repair and regeneration. Simultaneously, CLCF1 can regulate the efferocytosis function of macrophages, thus controlling the degree of inflammation and assisting in the repair of the damaged nervous system. In experiments, it was observed that targeting the regulation of macrophage CLCF1 expression led to improvements in memory, learning, and motor abilities in rats poisoned with CO.
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