Remodeling of senescent macrophages in synovium alleviates trauma- and aging-induced osteoarthritis
Yuhang Liu1, Jianan Duan2,3, Yifan Dang4,5
1Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 600 Yishan Rd, Shanghai, 200233, China.
Abstract:
Osteoarthritis (OA) is one of the most concerned aging-related diseases in the worldwide, yet the investigation of immune senescence in joint and related therapies are still poorly identified. Single-cell sequencing analysis and immunofluorescence of OA synovium reveal increased senescent macrophages in trauma-induced OA compared to controls. Importantly, senescent macrophages in OA synovium showed enhanced M1 polarization, mitochondrial damage and impaired efferocytosis, which could lead to increased senescence-associated secretory phenotypes (SASPs) in the joint and further exacerbate OA. Hence, a novel senotherapeutic nanoparticle is developed using chloroquine (CQ)-bearing polymers (pCQ) for targeted delivery of superoxide dismutase (SOD) to synovial macrophages, termed as pCQ/SOD. The nanoparticle achieves efficient intracellular delivery of SOD to synovial macrophages. RNA-seq results reveal that pCQ/SOD nanoparticle inhibits macrophage senescence via p53 and cellular senescence signaling pathway, further reprograms M1-to-M2 repolarization. Furthermore, the delivered SOD inhibits BAX-dependent mitochondrial outer membrane permeabilization (MOMP) which further reduces mitochondrial DNA (mtDNA) release and SASP secretion, while pCQ promotes macrophage efferocytosis against apoptotic cells via STAT3/ADAM17/MerTK signaling. As a result, intraarticular injection of pCQ/SOD nanoparticles in mice successfully alleviates not only trauma-induced OA, but aging-induced OA as well. The developed senotherapeutic nanoparticle in this study offers an effective approach for remodeling of senescent macrophages in synovium and a promising therapeutic strategy for OA treatment.
Insights
This study introduces a new nanoparticle therapy that targets senescent macrophages in osteoarthritis (OA) joints. The treatment effectively reduces inflammation and improves joint function, offering a promising new strategy for OA patients.
Area of Science:
- Immunology
- Gerontology
- Nanomedicine
Background:
- Osteoarthritis (OA) is a prevalent aging-related disease with poorly understood immune senescence mechanisms in joints.
- Senescent macrophages in OA synovium exhibit M1 polarization, mitochondrial damage, and impaired efferocytosis, contributing to disease progression via senescence-associated secretory phenotypes (SASPs).
Purpose of the Study:
- To investigate the role of senescent macrophages in osteoarthritis.
- To develop and evaluate a novel senotherapeutic nanoparticle for OA treatment targeting synovial macrophages.
Main Methods:
- Single-cell sequencing and immunofluorescence of OA synovium.
- Development of chloroquine (CQ)-bearing polymers loaded with superoxide dismutase (SOD) nanoparticles (pCQ/SOD).
- RNA sequencing (RNA-seq) to analyze the effects of pCQ/SOD on macrophage senescence and polarization.
- In vivo studies involving intraarticular injection of pCQ/SOD in mouse models of OA.
Main Results:
- Increased senescent macrophages with M1 polarization, mitochondrial damage, and reduced efferocytosis were observed in OA synovium.
- pCQ/SOD nanoparticles efficiently delivered SOD to synovial macrophages, inhibiting senescence via p53 and cellular senescence pathways and promoting M1-to-M2 repolarization.
- SOD inhibited BAX-dependent mitochondrial outer membrane permeabilization (MOMP), reducing mtDNA release and SASP secretion.
- CQ enhanced macrophage efferocytosis via STAT3/ADAM17/MerTK signaling.
- Intraarticular injection of pCQ/SOD alleviated both trauma-induced and aging-induced OA in mice.
Conclusions:
- Senescent macrophages play a critical role in osteoarthritis pathogenesis.
- The developed pCQ/SOD senotherapeutic nanoparticle effectively remodels senescent macrophages.
- This nanoparticle represents a promising therapeutic strategy for treating osteoarthritis by targeting immune senescence in the joint.
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