Olfactory ecto-mesenchymal stem cell-derived exosomes ameliorate murine Sj\xf6gren\u2019s syndrome by modulating the function of myeloid-derived suppressor cells

Ke Rui,Qiugang Zhu,Xiaofei Shi,Qing Yin,Xinfeng Wu,Xiaodan Kong,Shengjun Wang,Yida Xing,Hailong Fu,Jie Tian,Fan Xiao,Liwei Lu,Yue Hong,Huaxi Xu

doi:10.1038/s41423-020-00587-3

Abstract

Sjögren’s syndrome (SS) is a systemic autoimmune disease characterized by progressive inflammation and tissue damage in salivary glands and lacrimal glands. Our previous studies showed that myeloid-derived suppressor cells (MDSCs) exhibited impaired immunosuppressive function during disease progression in patients with SS and mice with experimental Sjögren’s syndrome (ESS), but it remains unclear whether restoring the function of MDSCs can effectively ameliorate the development of ESS. In this study, we found that murine olfactory ecto-mesenchymal stem cell-derived exosomes (OE-MSC-Exos) significantly enhanced the suppressive function of MDSCs by upregulating arginase expression and increasing ROS and NO levels. Moreover, treatment with OE-MSC-Exos via intravenous injection markedly attenuated disease progression and restored MDSC function in ESS mice. Mechanistically, OE-MSC-Exo-secreted IL-6 activated the Jak2/Stat3 pathway in MDSCs. In addition, the abundant S100A4 in OE-MSC-Exos acted as a key factor in mediating the endogenous production of IL-6 by MDSCs via TLR4 signaling, indicating an autocrine pathway of MDSC functional modulation by IL-6. Taken together, our results demonstrated that OE-MSC-Exos possess therapeutic potential to attenuate ESS progression by enhancing the immunosuppressive function of MDSCs, possibly constituting a new strategy for the treatment of Sjögren’s syndrome and other autoimmune diseases.

Highlights

Sjögren’s syndrome (SS) is characterized by progressive inflammation and tissue damage in salivary glands (SGs) and lacrimal glands.[1]
Isolation and identification of exosomes secreted from OE-mesenchymal stem cells (MSCs) and bone marrow mesenchymal stem cells (BM-MSCs) To characterize MSC-Exos, vesicle samples harvested from culture supernatants of Olfactory ecto-mesenchymal stem cells (OE-MSCs) and BM-MSCs were morphologically assessed by SEM and TEM
OE-MSC-Exos efficiently promote Myeloid-derived suppressor cells (MDSCs) differentiation with enhanced suppressive function We examined whether OE-MSC-Exos can regulate the differentiation and function of MDSCs in culture

Summary

Introduction

Sjögren’s syndrome (SS) is characterized by progressive inflammation and tissue damage in salivary glands (SGs) and lacrimal glands.[1] much progress has been made in elucidating the pathophysiological mechanisms underlying SS, the etiology of this disease is still unclear. It has been reported that SS is associated with an imbalance of T helper (Th1)/Th2 cells, but recent studies have demonstrated that Th17 cells, T follicular helper cells, and T follicular regulatory cells participate in the development of SS.[2,3] As a histopathological hallmark of SS, various types of immune cells infiltrate SG tissue and secrete many inflammatory cytokines, such as IL-1β, IFN-γ, and TNF-α, leading to tissue destruction and functional loss of the SG.[4].

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Conclusion