Olfactory ecto-mesenchymal stem cell-derived exosomes ameliorate murine Sjögren’s syndrome by modulating the function of myeloid-derived suppressor cells

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.

Treatment of Sjögren’s Syndrome with Mesenchymal Stem Cells: A Systematic Review

“…The method of MSC transplantation in mice and humans appeared to be broadly consistent across the studies. Intravenous injections of MSCs were used in all studies [ 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 ], with the exception of one [ 30 ] in which MSCs were administered intraperitoneally. A variety of cocultures were used such as UCMSCs cocultured with peripheral blood mononuclear cells (PBMCs) [ 31 , 32 ], and MSCs cocultured with monocyte-derived dendritic cells [ 26 ] or CD4 + T cells and MSC coculture experiments [ 33 ].…”

“…In type 2 diabetes, this cytokine exerts a protective effect by limiting inflammation, and in SS studies, it appeared to have a favorable role. Its role was not beneficial in other pathological conditions [ 25 ]. OE-MSCs injected in mice inhibited disease progression.…”

“…Thus, OE-MSCs induced IL-6 production by myeloid suppressor cells (MDSCs) via toll-like receptor 4 (TLR4) signaling. IL-6 is thus involved in improving the immunosuppressive function of MDSCs with an increase in the production of NO, ROS, and arginase [ 25 ]. Another study focusing on MDSCs showed an improvement in MDSC immunosuppressive capacities with increased arginase and NO after their injection in mouse models.…”

Effects of Mesenchymal Stem Cell-Derived Exosomes on Autoimmune Diseases

“…Interestingly, MSC-EXOs also enhanced the immunosuppressive function of macrophage precursor, which is called myeloid-derived suppressor cells (MDSCs), a heterogeneous population of immature Myeloid derived cells. IL-6 secreted by olfactory ecto-mesenchymal stem cell-derived exosomes (OE-MSC-EXOs) activates the JAK2/STAT3 pathway in MDSCs, and enhances the inhibitory function of MDSCs by upregulating the levels of arginase, ROS and NO ( 54 ). In addition, abundant S100A4 in OE-MSC-EXOs mediated endogenous IL-6 production of MDSCs through TLR4 signaling, and along with exosomal-derived IL-6 promotes the immunosuppressive function of MDSC ( 54 ).…”

“…IL-6 secreted by olfactory ecto-mesenchymal stem cell-derived exosomes (OE-MSC-EXOs) activates the JAK2/STAT3 pathway in MDSCs, and enhances the inhibitory function of MDSCs by upregulating the levels of arginase, ROS and NO ( 54 ). In addition, abundant S100A4 in OE-MSC-EXOs mediated endogenous IL-6 production of MDSCs through TLR4 signaling, and along with exosomal-derived IL-6 promotes the immunosuppressive function of MDSC ( 54 ).…”