Down-regulated GAS6 impairs synovial macrophage efferocytosis andpromotes obesity-associated osteoarthritis
Abstract
Obesity has always been considered a significant risk factor in OA progression, but the underlying mechanism of obesity-related inflammation in OA synovitis remains unclear. The present study found that synovial macrophages infiltrated and polarized in the obesity microenvironment and identified the essential role of M1 macrophages in impaired macrophage efferocytosis using pathology analysis of obesity-associated OA. The present study revealed that obese OA patients and Apoe-/- mice showed a more pronounced synovitis and enhanced macrophage infiltration in synovial tissue, accompanied by dominant M1 macrophage polarization. Obese OA mice had a more severe cartilage destruction and increased levels of synovial apoptotic cells than OA mice in the control group. Enhanced M1-polarized macrophages in obese synovium decreased growth arrest-specific 6 (GAS6) secretion, resulting in impaired macrophage efferocytosis in synovial apoptotic cells. Intracellular contents released by accumulated apoptotic cells further triggered an immune response and lead to a release of inflammatory factors, such as TNF-α, IL-1β, and IL-6, which induce chondrocyte homeostasis dysfunction in obese OA patients. Intra-articular injection of GAS6 restored the phagocytic capacity of macrophages, reduced the accumulation of local apoptotic cells, and decreased the levels of TUNEL- and caspase-3-positive cells, preserving cartilage thickness and preventing the progression of obesity-associated OA. Therefore, targeting macrophage associated efferocytosis or intra-articular injection of GAS6 is a potential therapeutic strategy for obesity-associated OA.
Data availability
Sequencing data have been deposited in GEO under accession codes GSE53986. Source Data has been uploaded in Dryad , which was named after "Down-regulated GAS6 impairs synovial macrophage efferocytosis and promotes obesity-associated osteoarthritis" https://doi.org/10.5061/dryad.d2547d86d.)
-
Down-regulated GAS6 impairs synovial macrophage efferocytosis and promotes obesity-associated osteoarthritisDryad Digital Repository, doi:10.5061/dryad.d2547d86d.
-
NRROS negatively regulates ROS in phagocytes during host defense and autoimmunityNCBI Gene Expression Omnibus, GSE53986.
Article and author information
Author details
Funding
National Natural Science Foundation of China (81902229)
- Haiyan Zhang
National Natural Science Foundation of China (81871745)
- Anling Liu
Natural Science Foundation of Guangdong Province (2020A1515011062)
- Haiyan Zhang
This work were fully funded by National Natural Science Foundation of China (NSFC).
Reviewing Editor
- Di Chen, Chinese Academy of Sciences, China
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in Chinese Laboratory animal-Guideline for ethical review of animal welfare (GB/T 35892-2018). The protocol was approved by the Southern Medical University Animal Care and Use Review Board(Permit Number: 2021- Ethical review-053). All surgery was performed under sodium pentobarbital anesthesia, and every effort was made to minimize suffering.
Human subjects: Informed consent was obtained from all recruited patients and was identified by the ethics committee of the Third Affiliated Hospital of Southern Medical University.
Version history
- Received: August 30, 2022
- Preprint posted: September 21, 2022 (view preprint)
- Accepted: May 4, 2023
- Accepted Manuscript published: May 5, 2023 (version 1)
- Version of Record published: May 17, 2023 (version 2)
Copyright
© 2023, Yao et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 1,200
- views
-
- 325
- downloads
-
- 9
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Further reading
-
- Evolutionary Biology
- Immunology and Inflammation
CD4+ T cell activation is driven by five-module receptor complexes. The T cell receptor (TCR) is the receptor module that binds composite surfaces of peptide antigens embedded within MHCII molecules (pMHCII). It associates with three signaling modules (CD3γε, CD3δε, and CD3ζζ) to form TCR-CD3 complexes. CD4 is the coreceptor module. It reciprocally associates with TCR-CD3-pMHCII assemblies on the outside of a CD4+ T cells and with the Src kinase, LCK, on the inside. Previously, we reported that the CD4 transmembrane GGXXG and cytoplasmic juxtamembrane (C/F)CV+C motifs found in eutherian (placental mammal) CD4 have constituent residues that evolved under purifying selection (Lee et al., 2022). Expressing mutants of these motifs together in T cell hybridomas increased CD4-LCK association but reduced CD3ζ, ZAP70, and PLCγ1 phosphorylation levels, as well as IL-2 production, in response to agonist pMHCII. Because these mutants preferentially localized CD4-LCK pairs to non-raft membrane fractions, one explanation for our results was that they impaired proximal signaling by sequestering LCK away from TCR-CD3. An alternative hypothesis is that the mutations directly impacted signaling because the motifs normally play an LCK-independent role in signaling. The goal of this study was to discriminate between these possibilities. Using T cell hybridomas, our results indicate that: intracellular CD4-LCK interactions are not necessary for pMHCII-specific signal initiation; the GGXXG and (C/F)CV+C motifs are key determinants of CD4-mediated pMHCII-specific signal amplification; the GGXXG and (C/F)CV+C motifs exert their functions independently of direct CD4-LCK association. These data provide a mechanistic explanation for why residues within these motifs are under purifying selection in jawed vertebrates. The results are also important to consider for biomimetic engineering of synthetic receptors.
-
- Genetics and Genomics
- Immunology and Inflammation
Transposable elements (TEs) are repetitive sequences representing ~45% of the human and mouse genomes and are highly expressed by medullary thymic epithelial cells (mTECs). In this study, we investigated the role of TEs on T-cell development in the thymus. We performed multiomic analyses of TEs in human and mouse thymic cells to elucidate their role in T-cell development. We report that TE expression in the human thymus is high and shows extensive age- and cell lineage-related variations. TE expression correlates with multiple transcription factors in all cell types of the human thymus. Two cell types express particularly broad TE repertoires: mTECs and plasmacytoid dendritic cells (pDCs). In mTECs, transcriptomic data suggest that TEs interact with transcription factors essential for mTEC development and function (e.g., PAX1 and REL), and immunopeptidomic data showed that TEs generate MHC-I-associated peptides implicated in thymocyte education. Notably, AIRE, FEZF2, and CHD4 regulate small yet non-redundant sets of TEs in murine mTECs. Human thymic pDCs homogenously express large numbers of TEs that likely form dsRNA, which can activate innate immune receptors, potentially explaining why thymic pDCs constitutively secrete IFN ɑ/β. This study highlights the diversity of interactions between TEs and the adaptive immune system. TEs are genetic parasites, and the two thymic cell types most affected by TEs (mTEcs and pDCs) are essential to establishing central T-cell tolerance. Therefore, we propose that orchestrating TE expression in thymic cells is critical to prevent autoimmunity in vertebrates.