PMID- 35332841 OWN - NLM STAT- MEDLINE DCOM- 20220825 LR - 20220825 IS - 1532-4311 (Electronic) IS - 0882-0139 (Linking) VI - 51 IP - 6 DP - 2022 Aug TI - Mesenchymal Stem Cells-derived Exosomes Ameliorate Lupus by Inducing M2 Macrophage Polarization and Regulatory T Cell Expansion in MRL/lpr Mice. PG - 1785-1803 LID - 10.1080/08820139.2022.2055478 [doi] AB - Previous studies have implicated that the transplantation of human umbilical cord mesenchymal stem cells (hUC-MSCs) effectively alleviates systemic lupus erythematosus (SLE) primarily due to immunomodulatory effects. However, little is known about the role of hUC-MSC-derived exosomes in SLE. This study is carried out to investigate the modifying effects of hUC-MSC-exosomes on the differentiation and function of immune cells in SLE. hUC-MSC-derived exosomes were extracted from the cultural supernatant of hUC-MSCs by ultrahigh speed centrifugation. Quantitative real-time polymerase chain reaction, western blot, enzyme-linked immunosorbent assay, and flow cytometry were performed to estimate the effect of hUC-MSC-derived exosomes on macrophage and regulatory T cell (Treg) polarization. In vivo, hUC-MSC-exosomes were injected intravenously into 28-week-old MRL/lpr mice. We had found that exosomes derived from hUC-MSC restrained the proliferation and inflammation of macrophages in vitro. Besides, MSC-exosomes inhibited CD68(+)M1 and HLA-DR(+)M1 but promoted CD206(+)M2 and CD163(+)M2 in vitro. Moreover, MRL/lpr mice administrated by intravenous injection of MSC-exosomes had less infiltration of CD14(+)CD11c(+)M1 cells but more CD14(+)CD163(+)M2 cells as well as Tregs in spleens compared with those in MRL/lpr mice treated by PBS. Additionally, MSC-exosomes could alleviate nephritis, liver and lung injuries of MRL/lpr mice. The survival of lupus mice could be improved after MSC-exosome treatment. This study has suggested that MSC-derived exosomes exert anti-inflammatory and immunomodulatory effects in SLE. MSC-exosomes ameliorate nephritis and other key organ injuries by inducing M2 macrophages and Tregs polarization. As natural nanocarriers, MSC-exosomes may serve as a promising cell-free therapeutic strategy for SLE.Abbreviations: SLE: Systemic lupus erythematosus; hUC-MSCs: Human umbilical cord mesenchymal stem cells; MSCs: Mesenchymal stem cells; qRT-PCR: Quantitative real-time polymerase chain reaction; ELISA: Enzyme-linked immunosorbent assay; Tregs: Regulatory cells; TNF-alpha: Tumor necrosis factor alfa; IL: Interleukin; COVID-19: Coronavirus disease 2019; pTHP-1: PMA-induced THP-1 macrophages; TEM: Transmission electron microscopy; LPS: Lipopolysaccharide; EVs: Extracellular vesicles; TRAF1: Tumor necrosis factor receptor-associated factor 1; IRAK1: Interferon-alpha-interleukin-1 receptor-associated kinase 1; NF-kappaB: Nuclear factor-kappaB; BLyS: B lymphocyte stimulator; APRIL: A proliferation-inducing ligand. FAU - Sun, Wenchang AU - Sun W AUID- ORCID: 0000-0001-7237-1511 AD - Central Laboratory of the First Affiliated Hospital, Weifang Medical University, Weifang, Shandong, China. FAU - Yan, Shushan AU - Yan S AUID- ORCID: 0000-0002-8194-6409 AD - Department of Gastrointestinal and Anal Diseases Surgery of the Affiliated Hospital, Weifang Medical University, Weifang, Shandong, China. FAU - Yang, Chunjuan AU - Yang C AUID- ORCID: 0000-0001-9320-0543 AD - Central Laboratory of the First Affiliated Hospital, Weifang Medical University, Weifang, Shandong, China. AD - Department of Rheumatology of the First Affiliated Hospital, Weifang Medical University, Weifang, Shandong, China. FAU - Yang, Jinghan AU - Yang J AUID- ORCID: 0000-0001-7577-2695 AD - Central Laboratory of the First Affiliated Hospital, Weifang Medical University, Weifang, Shandong, China. AD - Department of Rheumatology of the First Affiliated Hospital, Weifang Medical University, Weifang, Shandong, China. FAU - Wang, Hui AU - Wang H AUID- ORCID: 0000-0001-8789-2846 AD - Central Laboratory of the First Affiliated Hospital, Weifang Medical University, Weifang, Shandong, China. FAU - Li, Chaoran AU - Li C AD - Department of Rheumatology of the First Affiliated Hospital, Weifang Medical University, Weifang, Shandong, China. FAU - Zhang, Lili AU - Zhang L AUID- ORCID: 0000-0002-4616-2529 AD - Central Laboratory of the First Affiliated Hospital, Weifang Medical University, Weifang, Shandong, China. FAU - Zhao, Lu AU - Zhao L AUID- ORCID: 0000-0003-4636-5366 AD - Central Laboratory of the First Affiliated Hospital, Weifang Medical University, Weifang, Shandong, China. FAU - Zhang, Jiaojiao AU - Zhang J AD - Central Laboratory of the First Affiliated Hospital, Weifang Medical University, Weifang, Shandong, China. FAU - Cheng, Min AU - Cheng M AD - Department of Physiology, Weifang Medical University, Weifang, Shandong, China. FAU - Li, Xiangling AU - Li X AUID- ORCID: 0000-0002-2765-9708 AD - Department of Nephrology of Affiliated Hospital, Weifang Medical University, Weifang, Shandong, China. FAU - Xu, Donghua AU - Xu D AUID- ORCID: 0000-0002-9146-7858 AD - Central Laboratory of the First Affiliated Hospital, Weifang Medical University, Weifang, Shandong, China. AD - Department of Rheumatology of the First Affiliated Hospital, Weifang Medical University, Weifang, Shandong, China. LA - eng PT - Journal Article DEP - 20220325 PL - England TA - Immunol Invest JT - Immunological investigations JID - 8504629 RN - 0 (NF-kappa B) SB - IM MH - Animals MH - *COVID-19 MH - Cell Proliferation MH - *Exosomes MH - Humans MH - *Lupus Erythematosus, Systemic MH - Macrophages MH - *Mesenchymal Stem Cell Transplantation MH - *Mesenchymal Stem Cells MH - Mice MH - Mice, Inbred C57BL MH - Mice, Inbred MRL lpr MH - NF-kappa B MH - *Nephritis MH - T-Lymphocytes, Regulatory OTO - NOTNLM OT - Exosome OT - macrophage polarization OT - mesenchymal stem cell OT - regulatory T cell OT - systemic lupus erythematosus EDAT- 2022/03/26 06:00 MHDA- 2022/08/26 06:00 CRDT- 2022/03/25 08:37 PHST- 2022/03/26 06:00 [pubmed] PHST- 2022/08/26 06:00 [medline] PHST- 2022/03/25 08:37 [entrez] AID - 10.1080/08820139.2022.2055478 [doi] PST - ppublish SO - Immunol Invest. 2022 Aug;51(6):1785-1803. doi: 10.1080/08820139.2022.2055478. Epub 2022 Mar 25.