Immunomodulation by mesenchymal stem cells in treating human autoimmune disease-associated lung fibrosis

Abstract

BackgroundInterstitial pneumonia in connective tissue diseases (CTD-IP) featuring inflammation and fibrosis is a leading cause of death in CTD-IP patients. The related autoimmune lung injury and disturbed self-healing process make conventional anti-inflammatory drugs ineffective. Equipped with unique immunoregulatory and regenerative properties, mesenchymal stem cells (MSCs) may represent a promising therapeutic agent in CTD-IP. In this study, we aim to define the immunopathology involved in pulmonary exacerbation during autoimmunity and to determine the potential of MSCs in correcting these disorders.MethodsLung and blood specimens, bronchoalveolar lavage fluid cells collected from CTD-IP patients, and human primary lung fibroblasts (HLFs) from patients pathologically diagnosed with usual interstitial pneumonia (UIP) and healthy controls were analyzed by histology, flow cytometry and molecular biology. T cell subsets involved in the process of CTD-IP were defined, while the regulatory functions of MSCs isolated from the bone marrow of normal individuals (HBMSCs) on cytotoxic T cells and CTD-UIP HLFs were investigated in vitro.ResultsHigher frequencies of cytotoxic T cells were observed in the lung and peripheral blood of CTD-IP patients, accompanied with a reduced regulatory T cell (Treg) level. CTD-UIP HLFs secreted proinflammatory cytokines in combination with upregulation of α-smooth muscle actin (α-SMA). The addition of HBMSCs in vitro increased Tregs concomitant with reduced cytotoxic T cells in an experimental cell model with dominant cytotoxic T cells, and promoted Tregs expansion in T cell subsets from patients with idiopathic pulmonary fibrosis (IPF). HBMSCs also significantly decreased proinflammatory chemokine/cytokine expression, and blocked α-SMA activation in CTD-UIP HLFs through a TGF-β1-mediated mechanism, which modulates excessive IL-6/STAT3 signaling leading to IP-10 expression. MSCs secreting a higher level of TGF-β1 appear to have an optimal anti-fibrotic efficacy in BLM-induced pulmonary fibrosis in mice.ConclusionsImpairment of TGF-β signal transduction relevant to a persistent IL-6/STAT3 transcriptional activation contributes to reduction of Treg differentiation in CTD-IP and to myofibroblast differentiation in CTD-UIP HLFs. HBMSCs can sensitize TGF-β1 downstream signal transduction that regulates IL-6/STAT3 activation, thereby stimulating Treg expansion and facilitating anti-fibrotic IP-10 production. This may in turn block progression of lung fibrosis in autoimmunity.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-016-0319-y) contains supplementary material, which is available to authorized users.

Study on difference of peripheral serum SP-D, anti-MDA5, IL-6 and TNF-α in CTD-ILD patients

“…IL-6 is small-molecular glycopeptides secreted by activated T lymph cells. There are studies shows that IL-6 has close relations with fibrosis of pulmonary interstitium [16,17]. In this study, IL-6 level in serum of CTD-ILD and CTD patients higher than normal level obviously, IL-6 level of CTD-ILD patients higher than CTD patients (P<0.05).…”

Nab‐paclitaxel interrupts cancer‐stromal interaction through C‐X‐C motif chemokine 10‐mediated interleukin‐6 downregulation in vitro

“…29 Although it is commonly believed that antifibrosis of CXCL10 correlates to inhibit fibroblast migration, the effect of CXCL10 on αsmooth muscle actin and IL-6 expression to prevent myofibroblast differentiation is also reported. 30 In our study, after nab-PTX treatment, cancer cells increase CXCL10 expression, and this CXCL10 might decrease CAF IL-6 expression and suppress CAF tumor-promoting ability when the nab-PTX pretreated cancer cell-cultured medium was used to stimulate CAF.…”

Preconditioning with interleukin‐1 beta and interferon‐gamma enhances the efficacy of human umbilical cord blood‐derived mesenchymal stem cells‐based therapy via enhancing prostaglandin E2 secretion and indoleamine 2,3‐dioxygenase activity in dextran sulfate sodium‐induced colitis

“…It is also known that MSCs could exert immunoregulatory effects through different mechanisms, including immune cell interaction, production of soluble factors, and Treg generation (Liu et al, ). We confirmed that preconditioning hUCB‐MSCs with IL‐1β and IFN‐γ accelerated the secretion of IL‐10 and increased the differentiation of Tregs.…”