Dataset Information

Mesenchymal stem cell-derived exosome-educated macrophages alleviate systemic lupus erythematosus by promoting efferocytosis and recruitment of IL-17⁺ regulatory T cell.

ABSTRACT:

Background

Anti-inflammatory polarized macrophages are reported to alleviate systemic lupus erythematosus (SLE). Our previous studies have demonstrated that exosomes from adipose-derived stem cells promote the anti-inflammatory polarization of macrophages. However, the possible therapeutic effect of exosomes from stem cells on SLE remains unexplored.

Methods

Exosomes were isolated from the conditioned medium of bone marrow-derived mesenchymal stem cells using ultrafiltration and size-exclusion chromatography and were identified by nanoparticle tracking analysis and immunoblotting of exosomal-specific markers. Macrophages were collected from the MRL/lpr mouse kidney. The phenotype of macrophages was identified by immunoblotting for intracellular markers-inducible nitric oxide synthase (iNOS) and arginase-1 (Arg-1), and flow cytometry for macrophage markers F4/80, CD86, CD206, B7H4, and CD138. Pristane-induced murine lupus nephritis models were employed for in vivo study.

Results

When macrophages from the kidney of the MRL/lpr mice were treated with exosomes from bone marrow-derived mesenchymal stem cells (BM-MSCs), the upregulation of CD206, B7H4, CD138, Arg-1, CCL20, and anti-inflammatory cytokines was observed, which suggested that the macrophages were polarized to a specific anti-inflammatory phenotype. These anti-inflammatory macrophages produced low levels of reactive oxygen species (ROS) but had a high efferocytosis activity and promoted regulatory T (T_reg) cell recruitment. Moreover, exosome injection stimulated the anti-inflammatory polarization of macrophages and increased the production of IL-17⁺ T_reg cells in a pristane-induced murine lupus nephritis model. We observed that exosomes from BMMSCs depleted of microRNA-16 (miR-16) and microRNA-21 (miR-21) failed to downregulate PDCD4 and PTEN in macrophages, respectively, and attenuated exosome-induced anti-inflammatory polarization.

Conclusion

Our findings provide evidence that exosomes from BMMSCs promote the anti-inflammatory polarization of macrophages. These macrophages alleviate SLE nephritis in lupus mice by consuming apoptotic debris and inducing the recruitment of T_reg cells. We identify that exosomal delivery of miR-16 and miR-21 is a significant contributor to the polarization of macrophages.

SUBMITTER: Zhang M

PROVIDER: S-EPMC9509559 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Publications

Mesenchymal stem cell-derived exosome-educated macrophages alleviate systemic lupus erythematosus by promoting efferocytosis and recruitment of IL-17<sup>+</sup> regulatory T cell.

Zhang Mingchao M Johnson-Stephenson Takerra K TK Wang Weiran W Wang Yang Y Li Jing J Li Limin L Zen Ke K Chen Xi X Zhu Dihan D

Stem cell research & therapy 20220924 1

<h4>Background</h4>Anti-inflammatory polarized macrophages are reported to alleviate systemic lupus erythematosus (SLE). Our previous studies have demonstrated that exosomes from adipose-derived stem cells promote the anti-inflammatory polarization of macrophages. However, the possible therapeutic effect of exosomes from stem cells on SLE remains unexplored.<h4>Methods</h4>Exosomes were isolated from the conditioned medium of bone marrow-derived mesenchymal stem cells using ultrafiltration and s ...[more]

PMID: 36153633

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Project description:ObjectiveAutoantibody and inflammatory cytokines play crucial roles in the development of systemic lupus erythematosus (SLE); however, the regulation of their production warrants further investigation. This study aimed to investigate the role of basophil activation in the development of SLE based on studies in patients with SLE and spontaneous lupus-prone MRL-lpr/lpr mice.MethodsThe phenotypes of peripheral basophils and the production of autoantibody and interleukin (IL)-17 in patients with SLE were determined by flow cytometry and enzyme-linked immunosorbent assay, and also their correlations were investigated by statistical analysis. Thereafter, the effect of basophils on autoantibody production by B cells and Th17 differentiation in SLE were evaluated in vitro. Finally, the effect of basophil depletion on the development of autoimmune disorders in spontaneous lupus-prone MRL-lpr/lpr mice was examined.ResultsThe decreased numbers and an increased activation of peripheral basophils were found to be correlated with increased autoantibody production and disease activity in patients with SLE. Correspondingly, in vitro coculture studies showed that basophils obtained from patients with SLE promoted autoantibody production by SLE B cells and promoted Th17 differentiation from SLE naïve CD4+ T cells. The decrease of peripheral basophils in patients with SLE might be due to their migration to lymph nodes post their activation mediated by (autoreactive) IgE as supported by their increased CD62L and CCR7 expressions and accumulation in the lymph nodes of MRL-lpr/lpr mice. Furthermore, an increased activation of peripheral basophils was identified in MRL-lpr/lpr mice. Importantly, basophil-depleted MRL-lpr/lpr mice exhibited an extended life span, improved renal function, and lower serum levels of autoantibodies and IL-17, while basophil-adoptive-transferred mice exhibited the opposite results.ConclusionThese finding suggest that basophil activation-dependent autoantibody and IL-17 production may constitute a critical pathogenic mechanism in SLE.

Project description:BackgroundSystemic lupus erythematosus (SLE) is an autoimmune disorder in which excessive CD4+ T-cell activation and imbalanced effector T-cell differentiation play critical roles. Recent studies have implied a potential association between posttranscriptional N6-methyladenosine (m6A) modification and CD4+ T-cell-mediated humoral immunity. However, how this biological process contributes to lupus is not well understood. In this work, we investigated the role of the m6A methyltransferase like 3 (METTL3) in CD4+ T-cell activation, differentiation, and SLE pathogenesis both in vitro and in vivo.MethodsThe expression of METTL3 was knocked down and METTL3 enzyme activity was inhibited using siRNA and catalytic inhibitor, respectively. In vivo evaluation of METTL3 inhibition on CD4+ T-cell activation, effector T-cell differentiation, and SLE pathogenesis was achieved using a sheep red blood cell (SRBC)-immunized mouse model and a chronic graft versus host disease (cGVHD) mouse model. RNA-seq was performed to identify pathways and gene signatures targeted by METTL3. m6A RNA-immunoprecipitation qPCR was applied to confirm the m6A modification of METTL3 targets.ResultsMETTL3 was defective in the CD4+ T cells of SLE patients. METTL3 expression varied following CD4+ T-cell activation and effector T-cell differentiation in vitro. Pharmacological inhibition of METTL3 promoted the activation of CD4+ T cells and influenced the differentiation of effector T cells, predominantly Treg cells, in vivo. Moreover, METTL3 inhibition increased antibody production and aggravated the lupus-like phenotype in cGVHD mice. Further investigation revealed that catalytic inhibition of METTL3 reduced Foxp3 expression by enhancing Foxp3 mRNA decay in a m6A-dependent manner, hence suppressing Treg cell differentiation.ConclusionIn summary, our findings demonstrated that METTL3 was required for stabilizing Foxp3 mRNA via m6A modification to maintain the Treg differentiation program. METTL3 inhibition contributed to the pathogenesis of SLE by participating in the activation of CD4+ T cells and imbalance of effector T-cell differentiation, which could serve as a potential target for therapeutic intervention in SLE.

Dataset Information

Mesenchymal stem cell-derived exosome-educated macrophages alleviate systemic lupus erythematosus by promoting efferocytosis and recruitment of IL-17⁺ regulatory T cell.

Background

Methods

Results

Conclusion

Publications

Mesenchymal stem cell-derived exosome-educated macrophages alleviate systemic lupus erythematosus by promoting efferocytosis and recruitment of IL-17<sup>+</sup> regulatory T cell.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Mesenchymal stem cell-derived exosome-educated macrophages alleviate systemic lupus erythematosus by promoting efferocytosis and recruitment of IL-17+ regulatory T cell.

Background

Methods

Results

Conclusion

Publications

Mesenchymal stem cell-derived exosome-educated macrophages alleviate systemic lupus erythematosus by promoting efferocytosis and recruitment of IL-17<sup>+</sup> regulatory T cell.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Mesenchymal stem cell-derived exosome-educated macrophages alleviate systemic lupus erythematosus by promoting efferocytosis and recruitment of IL-17⁺ regulatory T cell.