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Impaired efferocytosis enables apoptotic osteoblasts to escape osteoimmune surveillance during aging

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE201651 | GEO | 2022/04/30

REPOSITORIES: GEO

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Impaired Efferocytosis Enables Apoptotic Osteoblasts to Escape Osteoimmune Surveillance During Aging.

Project description:Macrophage efferocytosis of apoptotic osteoblasts (apoOBs) is a key osteoimmune process for bone homeostasis. However, apoOBs frequently accumulate in aged bone marrow, where they may mount proinflammatory responses and progressive bone loss. The reason why apoOBs are not cleared during aging remains unclear. In this study, it is demonstrated that aged apoOBs upregulate the immune checkpoint molecule CD47, which is controlled by SIRT6-regulated transcriptional pausing, to evade clearance by macrophages. Using osteoblast- and myeloid-specific gene knockout mice, SIRT6 is further revealed to be a critical modulator for apoOBs clearance via targeting CD47-SIRPα checkpoint. Moreover, apoOBs activate SIRT6-mediated chemotaxis to recruit macrophages by releasing apoptotic vesicles. Two targeting delivery strategies are developed to enhance SIRT6 activity, resulting in rejuvenated apoOBs clearance and delayed age-related bone loss. Collectively, the findings reveal a previously unknown linkage between immune surveillance and bone homeostasis and targeting the SIRT6-regulated mechanism can be a promising therapeutic strategy for age-related bone diseases.

| S-EPMC10754079 | biostudies-literature

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)

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

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

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Impaired efferocytosis enables apoptotic osteoblasts to escape osteoimmune surveillance during aging

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

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

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