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Impaired efferocytosis enables apoptotic osteoblasts to escape osteoimmune surveillance during aging (mRNA)

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE213675 | GEO | 2022/09/22

REPOSITORIES: GEO

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Impaired efferocytosis enables apoptotic osteoblasts to escape osteoimmune surveillance during aging (mRNA)

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

Impaired efferocytosis enables apoptotic osteoblasts to escape osteoimmune surveillance during aging (miRNA)

2022-04-30 | GSE201649 | GEO

Impaired efferocytosis enables apoptotic osteoblasts to escape osteoimmune surveillance during aging (ChIP-seq)

2022-09-22 | GSE213674 | GEO

Engineered CD47 protects T cells for enhanced antitumor immunity

Project description:Adoptively transferred T cells and agents designed to block the CD47/SIRPalpha axis are promising cancer therapeutics that activate distinct arms of the immune system. We administered anti-CD47 with adoptively transferred T cells with the goal of enhancing antitumor efficacy but observed rapid macrophage-mediated clearance of T cells expressing chimeric antigen receptors (CARs) or engineered T cell receptors, which abrogated therapeutic benefit. anti-CD47 mediated CAR T clearance was potent and rapid enough to serve as an effective safety switch. To overcome this challenge, we engineered a CD47 variant (47E) that engaged SIRPalpha and provided a “don’t-eat-me” signal that was not blocked by anti-CD47 antibodies. TCR or CAR T cells expressing 47E were resistant to clearance by macrophages following anti-CD47, and mediated significant, sustained macrophage recruitment into the TME. Although many of the recruited macrophages manifested an M2-like profile, the combined therapy synergistically enhanced antitumor efficacy. This work identifies macrophages as major regulators of T cell persistence and illustrates the fundamental challenge of combining T cell directed therapeutics with those designed to activate macrophages. It further delivers a therapeutic approach capable of simultaneously harnessing the antitumor effects of T cells and macrophages that manifests enhanced potency against solid tumors.

2024-03-13 | GSE261475 | GEO

CD47-SIRPα axis blockade in NASH promotes necroptotic hepatocyte clearance by liver macrophages and decreases hepatic fibrosis

Project description:Necroptosis contributes to hepatocyte death (HC) in non-alcoholic steatohepatitis (NASH), but the fate and roles of necroptotic hepatocytes (necHCs) in NASH remain unknown. We show here that the accumulation of necHCs is associated with worsening NASH in humans and in mice with diet-induced NASH and that NASH liver showed evidence of impaired necHC clearance by liver macrophages. Further, the "don't-eat-me" ligand CD47 on HCs and its receptor, SIRPα, on liver macrophages, were markedly upregulated in human and mouse NASH. In vitro, anti-CD47 or anti-SIRPα promoted necHC engulfment by primary liver macrophages. In a proof-of-concept mouse model of inducible HC necroptosis, anti-CD47 increased necHC uptake by liver macrophages and inhibited hepatic stellate cell (HSC) activation, which is responsible for liver fibrogenesis. Most importantly, treatment of two mouse models of diet-induced NASH with anti-CD47 or anti-SIRPα increased the uptake of necHC by liver macrophages and decreased HSC activation and liver fibrosis. These findings provide evidence that impaired clearance of necHCs by liver macrophages due to CD47-SIRPα upregulation contributes to fibrotic NASH and suggest therapeutic blockade of the CD47-SIRPα axis as a strategy to decrease the accumulation of necHCs in NASH liver and dampen the progression of hepatic fibrosis.

2022-11-25 | GSE197111 | GEO

Macrophages induce inflammation by efferocytosis of apoptotic prostate cancer cells via HIF-1α stabilization

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

Transcriptomics of isolated alveolar macrophages from WT and CD47 deficient mice upon influenza A virus infection

Project description:CD47 is an ubiquitously expressed surface molecule that has a significant impact on immune responses. However, its role for antiviral immunity is not fully understood. We can show that CD47 has an inhibitory role in influenza virus defense, since CD47-deficient mice (CD47-/-) display an increased viral clearance during influenza virus infection. This effect is strongly associated with alveolar macrophages, yet the underlying mechanisms are unclear. Thus, to assess the precise impact of CD47 on antiviral action of alveolar macrophages, transcriptional analysis of ex vivo isolated alveolar macrophages from CD47-/- and WT mice were performed isolated 3dpi. Surprisingly, instead of classical antiviral mediators, an increased expression of both hemoglobin α and hemoglobin β was found in CD47 deficient compared to WT alveolar macrophages upon influenza A virus infection. Importantly, antiviral activity of hemoglobin was already shown for other viruses and thus, CD47 might limit influenza virus defense via the regulation of hemoglobin, which could act as a modulator of the antiviral immune response during the infection.

2022-12-09 | GSE201825 | GEO

Impaired efferocytosis enables apoptotic osteoblasts to escape osteoimmune surveillance during aging

Project description:Impaired efferocytosis enables apoptotic osteoblasts to escape osteoimmune surveillance during aging

| PRJNA832553 | ENA

Transcriptional profiling of young and old mouse macrophages interacting with nanoparticles [Bulk RNA-seq]

Project description:The mononuclear phagocytic system is integral to the clearance of nanotherapeutics. However, the precise mechanisms involved in the phagocytic clearance of nanotherapeutics, and how age-associated changes in innate immune cells affect this clearance, are poorly understood. We found that the ability of professional phagocytes to take up nanoparticles diminishes with age. Bulk RNA sequencing of bone marrow derived macrophages and single cell RNA sequencing of liver macrophages derived from young and old mice was carried out to investigate the gene expression changes that may be assiciated with the changed ability of macrophages to uptake nanoparticles.

2023-07-18 | GSE205826 | GEO

Transcriptional profiling of young and old mouse macrophages interacting with nanoparticles [scRNA-seq]

2023-07-18 | GSE205832 | GEO

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