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Mesenchymal stem cell transplantation alleviates experimental Sjogren's syndrome through IFN-?/IL-27 signaling axis.

ABSTRACT: Rationale: Although mesenchymal stem cell (MSC) transplantation has been proved to be an effective therapeutic approach to treat experimental Sjögren's syndrome (SS), the detailed underlying mechanisms remains unknown. IL-27 has diverse influences on the regulation of T cell differentiation and was involved in SS through modulating immune response. Here we aimed to explore whether IL-27-mediated regulation of immune cells was responsible for the beneficial effects of MSC transplantation on SS. Methods: The SS-like symptoms were evaluated in IL-27 deficient and recombinant IL-27-treated NOD mice. The MSCs were infused into NOD mice via the tail vein. The histological features of submandibular glands, saliva flow rate and serum IL-27 were examined. The effects of MSCs on the IL-27 production and Th17/Treg cell in SS patients and mice in vitro and in vivo were determined for the mechanistic study. Results: This study showed that SS patients had decreased IL-27 level and increased ratio of Th17/Treg cells. Consistently, exacerbated SS-like symptoms were observed in IL-27 deficient NOD mice, along with increased ratio of Th17/Treg cells. Importantly, MSC transplantation alleviated SS-like symptoms by elevating the level of IL-27 to restore Th17/Treg balance in NOD mice. Mechanistically, MSC-secreted interferon-? (IFN-?) promote dendritic cells to produce IL-27. Conclusions: Thus, we have revealed a previously unrecognized function of MSC-mediated IL-27 production by DCs in suppressing SS-like syndrome, which provided evidences for clinical application of MSC in patients with SS.

SUBMITTER: Yao G

PROVIDER: S-EPMC6857067 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Mesenchymal stem cell transplantation alleviates experimental Sjögren's syndrome through IFN-β/IL-27 signaling axis.

Yao Genhong G Qi Jingjing J Liang Jun J Shi Bingyu B Chen Weiwei W Li Wenchao W Tang Xiaojun X Wang Dandan D Lu Liwei L Chen Wanjun W Shi Songtao S Hou Yayi Y Sun Lingyun L

Theranostics 20191021 26

<b>Rationale</b>: Although mesenchymal stem cell (MSC) transplantation has been proved to be an effective therapeutic approach to treat experimental Sjögren's syndrome (SS), the detailed underlying mechanisms remains unknown. IL-27 has diverse influences on the regulation of T cell differentiation and was involved in SS through modulating immune response. Here we aimed to explore whether IL-27-mediated regulation of immune cells was responsible for the beneficial effects of MSC transplantation o ...[more]

PMID: 31754394

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Project description:IntroductionSjögren's syndrome (SjS) is a systemic autoimmune disease characterized by decreased salivary and lacrimal gland secretions, resulting in severe dry mouth and dry eyes. Recent studies have suggested that TH17 cells and its signature cytokine IL-17 are involved in the underlying pathogenic mechanisms leading to destructive inflammation and autoimmunity. In the present study, we examined whether IL-27, a natural inhibitor of TH17 activity, could down-regulate or reverse SjS in C57BL/6.NOD-Aec1Aec2 mice, a model of primary-SjS.MethodsRecombinant serotype 2 adeno-associated viral (AAV2) vectors expressing either IL-27 (rAAV2-IL27) or LacZ (rAAV2-LacZ) were injected into 6 or 14 week-old C57BL/6.NOD-Aec1Aec2 mice. Changes in IL-27, IL-17, and IL-10 cytokine levels in peripheral blood were determined by ELISAs, while flow cytometry analyses were used to quantify cytokine-positive splenocytes. Histological assessment of salivary glands, anti-nuclear autoantibody (ANA) staining, and stimulated saliva flow rates were used to profile SjS disease severity.ResultsMice systemically treated with intravenous rAAV2-IL27 injections at either 6 or 14 weeks of age exhibited long-term elevated levels of serum IL-27 with concomitantly reduced levels of IL-17 compared with sera from mice injected with rAAV2-LacZ or saline out to 20 weeks post-inoculation. Most importantly, disease profiles revealed that rAAV2-IL27 treatment had little effect on lymphocytic focus (LF) scores, but resulted in structural changes in LF, lower titers of ANAs with changes in staining patterns, and a less severe clinical disease as determined by saliva flow rates.ConclusionsThese data support the concept that IL-27, when provided exogenously, can induce a suppressive effect on SjS development and thus may be an effective therapeutic agent for regulating TH17 pro-inflammatory activity in autoimmune diseases where the TH17 system has been shown to play an important role in their pathogenesis.

Project description:Intact and broad immune cell effector functions and specific individual cytokines have been linked to HIV disease outcome, but their relative contribution to HIV control remains unclear. We asked whether the proteome of secreted cytokines and signaling factors in peripheral blood can be used to discover specific pathways critical for host viral control. A custom glass-based microarray, able to measure >600 plasma proteins involved in cell-to-cell communication, was used to measure plasma protein profiles in 96 HIV-infected, treatment-naive individuals with high (>50,000) or low (<10,000 HIV RNA copies/ml) viral loads. Univariate and regression model analysis demonstrate that plasma levels of soluble interleukin-27 (IL-27) are significantly elevated in individuals with high plasma viremia (P < 0.0001) and are positively correlated with proviral HIV-DNA copy numbers in peripheral blood mononuclear cells (PBMC) (Rho = 0.4011; P = 0.0027). Moreover, soluble IL-27 plasma levels are negatively associated with the breadth and magnitude of the total virus-specific T-cell responses and directly with plasma levels of molecules involved in Wnt/?-catenin signaling. In addition to IL-27, gene expression levels of the specific IL-27 receptor (IL27RA) in PBMC correlated directly with both plasma viral load (Rho = 0.3531; P = 0.0218) and the proviral copy number in the peripheral blood as an indirect measure of partial viral reservoir (Rho = 0.4580; P = 0.0030). These results were validated in unrelated cohorts of early infected subjects as well as subjects before and after initiation of antiretroviral treatment, and they identify IL-27 and its specific receptor as a critical immune axis for the antiviral immune response and as robust correlates of viral load and proviral reservoir size in PBMC.IMPORTANCE The detailed knowledge of immune mechanisms that contribute to HIV control is a prerequisite for the design of effective treatment strategies to achieve HIV cure. Cells communicate with each other by secreting signaling proteins, and the blood is a key conduit for transporting such factors. Investigating the communication factors promoting effective immune responses and having potentially antiviral functions against HIV using a novel focused omics approach ("communicome") has the potential to significantly improve our knowledge of effective host immunity and accelerate the HIV cure agenda. Including 140 subjects with variable viral loads and measuring the plasma levels of >600 soluble proteins, our data highlight the importance of Th17 cells and Wnt/?-catenin signaling in HIV control and especially identify the IL-27/IL-27 receptor subunit alpha (IL-27RA) axis as a predictor of plasma viral load and proviral copy number in the peripheral blood. These data may provide important guidance to therapeutic approaches in the HIV cure agenda.

Dataset Information

Mesenchymal stem cell transplantation alleviates experimental Sjogren's syndrome through IFN-?/IL-27 signaling axis.

Publications

Mesenchymal stem cell transplantation alleviates experimental Sjögren's syndrome through IFN-β/IL-27 signaling axis.

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