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Mesenchymal stem cells alleviate LPS-induced acute lung injury by inhibiting the proinflammatory function of Ly6C+ CD8+ T cells.

ABSTRACT: Systemic inflammatory processes, including alveolar injury, cytokine induction, and neutrophil accumulation, play key roles in the pathophysiology of acute lung injury (ALI). The immunomodulatory effects of mesenchymal stem cells (MSCs) can contribute to the treatment of inflammatory disorders. In previous studies, the focus was on innate immune cells and the effects of MSCs on ALI through CD8+ T cells remain unclear. In the present study, lipopolysaccharide (LPS) was used to induce ALI in mice. ALI mice were treated with MSCs via intratracheal instillation. Survival rate, histopathological changes, protein levels, total cell count, cytokine levels, and chemokine levels in alveolar lavage fluid were used to determine the efficacy of MSCs. Mass cytometry and single-cell RNA sequencing (scRNA-seq) were used to characterize the CD8+ T cells in the lungs. Ly6C- CD8+ T cells are prevalent in normal mice, whereas a specialized effector phenotype expressing a high level of Ly6C is predominant in advanced disease. MSCs significantly mitigated ALI and improved survival. MSCs decreased the infiltration of CD8+ T cells, especially Ly6C+ CD8+ T cells into the lungs. Mass cytometry revealed that CD8+ T cells expressing high Ly6C and CXCR3 levels caused tissue damage in the lungs of ALI mice, which was alleviated by MSCs. The scRNA-seq showed that Ly6C+ CD8+ T cells exhibited a more activated phenotype and decreased expression of proinflammatory factors that were enriched the most in immune chemotaxis after treatment with MSCs. We showed that CD8+ T cells play an important role in MSC-mediated ALI remission, and both infiltration quantity and proinflammatory function were inhibited by MSCs, indicating a potential mechanism for therapeutic intervention.

SUBMITTER: Zhu J

PROVIDER: S-EPMC7538431 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Mesenchymal stem cells alleviate LPS-induced acute lung injury by inhibiting the proinflammatory function of Ly6C+ CD8+ T cells.

Zhu Jiaqi J Feng Bing B Xu Yanping Y Chen Wenyi W Sheng Xinyu X Feng Xudong X Shi Xiaowei X Liu Jingqi J Pan Qiaoling Q Yu Jiong J Li Lanjuan L Cao Hongcui H

Cell death & disease 20201006 10

Systemic inflammatory processes, including alveolar injury, cytokine induction, and neutrophil accumulation, play key roles in the pathophysiology of acute lung injury (ALI). The immunomodulatory effects of mesenchymal stem cells (MSCs) can contribute to the treatment of inflammatory disorders. In previous studies, the focus was on innate immune cells and the effects of MSCs on ALI through CD8+ T cells remain unclear. In the present study, lipopolysaccharide (LPS) was used to induce A ...[more]

PMID: 33024074

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Project description:Acute lung injury (ALI) is an inflammatory disease associated with alveolar injury, subsequent macrophage activation, inflammatory cell infiltration, and cytokine production. Mesenchymal stem cells (MSCs) are beneficial for application in the treatment of inflammatory diseases due to their immunomodulatory effects. However, the mechanisms of regulatory effects by MSCs on macrophages in ALI need more in-depth study. Lung tissues were collected from mice for mouse lung organoid construction. Alveolar macrophages (AMs) derived from bronchoalveolar lavage and interstitial macrophages (IMs) derived from lung tissue were co-cultured, with novel matrigel-spreading lung organoids to construct an in vitro model of lung organoids-immune cells. Mouse compact bone-derived MSCs were co-cultured with organoids-macrophages to confirm their therapeutic effect on acute lung injury. Changes in transcriptome expression profile were analyzed by RNA sequencing. Well-established lung organoids expressed various lung cell type-specific markers. Lung organoids grown on spreading matrigel had the property of functional cells growing outside the lumen. Lipopolysaccharide (LPS)-induced injury promoted macrophage chemotaxis toward lung organoids and enhanced the expression of inflammation-associated genes in inflammation-injured lung organoids-macrophages compared with controls. Treatment with MSCs inhibited the injury progress and reduced the levels of inflammatory components. Furthermore, through the nuclear factor-κB pathway, MSC treatment inhibited inflammatory and phenotypic transformation of AMs and modulated the antigen-presenting function of IMs, thereby affecting the inflammatory phenotype of lung organoids. Lung organoids grown by spreading matrigel facilitate the reception of external stimuli and the construction of in vitro models containing immune cells, which is a potential novel model for disease research. MSCs exert protective effects against lung injury by regulating different functions of AMs and IMs in the lung, indicating a potential mechanism for therapeutic intervention.

Project description:BackgroundSince gamma delta (γδ) T cells are involved in various autoimmune diseases, we aimed to verify whether γδ T cells participate in the pathogenesis of Sjögren's syndrome (SS) and related pulmonary inflammation, and also aimed to evaluate the effects of umbilical cord mesenchymal stem cells (MSCs) on SS-related pulmonary inflammation and the γδ T cells.MethodsThe saliva flow rates of female non-obese diabetic (NOD/Ltj) mice were measured. Histopathologic analysis was performed in salivary glands (SG) and lung tissues. The levels of γδ T cells and their subsets in the peripheral blood, spleen, and lung were examined by flow cytometry. The purified γδ T cells were adoptively transferred into NOD/Ltj mice. MSC transplantation was performed in 8-week-old NOD/Ltj mice.ResultsThe results showed lymphocytic infiltration in SG and lacrimal glands (LG), and reduction of saliva flow rates in 8-week NOD/Ltj mice. The levels of γδ T cells decreased in peripheral blood, but increased in the lung of 8- and 12-week-old NOD/Ltj mice. The proportions and numbers of Vγ4+ T cells and Vγ4+ IL-17A+ T cells increased in the lung, but decreased in peripheral blood of 8-week-old NOD/Ltj mice. Notably, transfer of γδ T cells decreased the rate of saliva flow, as well as aggravated the pathological changes in the lung. The transplantation of MSCs increased saliva flow rate and alleviated pathological injury in the SG and lung. The frequencies of Vγ4+ T cells and Vγ4+ IL-17A+ T cells in the lung and spleen significantly decreased after MSC treatment. Our results demonstrated that γδ T cells and Vγ4+ T cells contribute to the pathogenesis of SS and SS-related pulmonary inflammation. In addition, MSCs relieved SS and SS-related pulmonary inflammation through suppressing Vγ4+ IL-17A+ T cells.ConclusionsPeripheral Vγ4+ T cells infiltrate into the lung in SS mice, and aggravate the symptoms of SS and SS-related pulmonary inflammation by secreting IL-17A. Meanwhile, lymphocyte infiltration could be reversed by MSC transplantation, which indicates the potential of MSCs in the treatment of SS and SS-related pulmonary inflammation patients.

Dataset Information

Mesenchymal stem cells alleviate LPS-induced acute lung injury by inhibiting the proinflammatory function of Ly6C+ CD8+ T cells.

Publications

Mesenchymal stem cells alleviate LPS-induced acute lung injury by inhibiting the proinflammatory function of Ly6C<sup>+</sup> CD8<sup>+</sup> T cells.

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