Impaired efferocytosis enables apoptotic osteoblasts to escape osteoimmune surveillance during aging
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ABSTRACT:
PROVIDER: PRJNA832553 | ENA |
REPOSITORIES: ENA
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Project description:Impaired efferocytosis enables apoptotic osteoblasts to escape osteoimmune surveillance during aging (mRNA)
| PRJNA832555 | ENA
Project description:Impaired efferocytosis enables apoptotic osteoblasts to escape osteoimmune surveillance during aging (miRNA)
| PRJNA832556 | ENA
Project description:Macrophages efferocytosis of apoptotic osteoblasts (apoOBs) is a key osteoimmune process for bone homeostasis that is highly regulated in osteoimmune surveillance. However, apoOBs accumulate in aged bone marrow, where they might mount proinflammatory responses and progressive bone loss. Why apoOBs were not cleared during aging remains unknown. Here, we show that apoOBs upregulate immune checkpoint molecule CD47 with age to evade macrophages clearance. Using osteoblast- and myeloid-specific gene knockout mice, we identify histone deacetylase SIRT6 as an essential regulator of the CD47–SIRPα checkpoint. Further, apoOBs that require SIRT6-mediated chemotaxis signals can recruit macrophages by releasing apoptotic extracellular vesicles. Therapeutically, we develop two targeting delivery strategies to enhance SIRT6 activity, showing increased apoOBs clearance and delayed age-related bone loss. Collectively, our data revealed a previously unknown linkage between immune surveillance and bone homeostasis and targeting the mechanism of SIRT6-regulated apoOBs clearance could be a promising therapeutic strategy for age-related bone diseases.
2022-09-22 | GSE213675 | GEO
Project description:Macrophages efferocytosis of apoptotic osteoblasts (apoOBs) is a key osteoimmune process for bone homeostasis that is highly regulated in osteoimmune surveillance. However, apoOBs accumulate in aged bone marrow, where they might mount proinflammatory responses and progressive bone loss. Why apoOBs were not cleared during aging remains unknown. Here, we show that apoOBs upregulate immune checkpoint molecule CD47 with age to evade macrophages clearance. Using osteoblast- and myeloid-specific gene knockout mice, we identify histone deacetylase SIRT6 as an essential regulator of the CD47–SIRPα checkpoint. Further, apoOBs that require SIRT6-mediated chemotaxis signals can recruit macrophages by releasing apoptotic extracellular vesicles. Therapeutically, we develop two targeting delivery strategies to enhance SIRT6 activity, showing increased apoOBs clearance and delayed age-related bone loss. Collectively, our data revealed a previously unknown linkage between immune surveillance and bone homeostasis and targeting the mechanism of SIRT6-regulated apoOBs clearance could be a promising therapeutic strategy for age-related bone diseases.
2022-04-30 | GSE201650 | GEO
Project description:Macrophages efferocytosis of apoptotic osteoblasts (apoOBs) is a key osteoimmune process for bone homeostasis that is highly regulated in osteoimmune surveillance. However, apoOBs accumulate in aged bone marrow, where they might mount proinflammatory responses and progressive bone loss. Why apoOBs were not cleared during aging remains unknown. Here, we show that apoOBs upregulate immune checkpoint molecule CD47 with age to evade macrophages clearance. Using osteoblast- and myeloid-specific gene knockout mice, we identify histone deacetylase SIRT6 as an essential regulator of the CD47–SIRPα checkpoint. Further, apoOBs that require SIRT6-mediated chemotaxis signals can recruit macrophages by releasing apoptotic extracellular vesicles. Therapeutically, we develop two targeting delivery strategies to enhance SIRT6 activity, showing increased apoOBs clearance and delayed age-related bone loss. Collectively, our data revealed a previously unknown linkage between immune surveillance and bone homeostasis and targeting the mechanism of SIRT6-regulated apoOBs clearance could be a promising therapeutic strategy for age-related bone diseases.
2022-04-30 | GSE201649 | GEO
Project description:Macrophages efferocytosis of apoptotic osteoblasts (apoOBs) is a key osteoimmune process for bone homeostasis that is highly regulated in osteoimmune surveillance. However, apoOBs accumulate in aged bone marrow, where they might mount proinflammatory responses and progressive bone loss. Why apoOBs were not cleared during aging remains unknown. Here, we show that apoOBs upregulate immune checkpoint molecule CD47 with age to evade macrophages clearance. Using osteoblast- and myeloid-specific gene knockout mice, we identify histone deacetylase SIRT6 as an essential regulator of the CD47–SIRPα checkpoint. Further, apoOBs that require SIRT6-mediated chemotaxis signals can recruit macrophages by releasing apoptotic extracellular vesicles. Therapeutically, we develop two targeting delivery strategies to enhance SIRT6 activity, showing increased apoOBs clearance and delayed age-related bone loss. Collectively, our data revealed a previously unknown linkage between immune surveillance and bone homeostasis and targeting the mechanism of SIRT6-regulated apoOBs clearance could be a promising therapeutic strategy for age-related bone diseases.
2022-09-22 | GSE213674 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2022-04-30 | GSE201651 | 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:Clearance of apoptotic cancer cells by macrophages, known as efferocytosis, fuels the bone-metastatic growth of prostate cancer cells via pro-inflammatory and immunosuppressive mechanisms that are still unclear. In this study, single-cell transcriptomics of bone marrow macrophages undergoing efferocytosis of apoptotic prostate cancer cells revealed a significant enrichment of a cellular response to hypoxia. Here we show that efferocytic macrophages promote HIF-1α stabilization under normoxic conditions through interaction with phosphorylated STAT3. Inflammatory cytokine gene expression analysis of efferocytic HIF-1α-mutant macrophages revealed a reduced expression of the pro-tumorigenic Mif. Furthermore, stabilization of HIF-1α using the HIF-prolyl-hydroxylase inhibitor, Roxadustat, enhanced MIF expression in macrophages. Finally, macrophages treated with recombinant MIF protein activated NF-κB (p65) signaling increased the expression of pro-inflammatory cytokines. Altogether, these findings suggest that the clearance of apoptotic cancer cell by tumor-associated macrophages triggers p-STAT3/HIF-1α/MIF signaling to enhance tumor-promoting inflammation in bone, suggesting this axis as a target for metastatic prostate cancer.
2022-12-14 | GSE180638 | 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