Resolution acute respiratory distress syndrome through reversing the imbalance of Treg/Th17 by targeting the cAMP signaling pathway

Li, Qian; Hu, Xiuping; Sun, Renhua; Tu, Yuexing; Gong, Fangxiao; Yin, Ning

doi:10.3892/mmr.2016.5222

Cited by 27 publications

(25 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Therefore, regulation of CD4 + CD25 + Foxp3 + Tregs and Th17 cells may promote the recovery of ALI/ARDS. A murine study has found that reversal of the imbalance of Treg/Th17 by targeting the cAMP signalling pathway promoted resolution of ARDS …”

Section: Introductionmentioning

confidence: 99%

“…A murine study has found that reversal of the imbalance of Treg/Th17 by targeting the cAMP signalling pathway promoted resolution of ARDS. 9 The objective of our study was to investigate if recovery from lung injury can be promoted by the modulation of CD4 + CD25 + Foxp3 + Tregs and Th17 cells. In the wellestablished model of intratracheal lipopolysaccharide (LPS)-induced lung injury, we modulated Treg numbers by CD25 depletion and TGF-β neutralization, and Th17 cell abundance by IL-17A and IL-22 neutralization.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Recovery from acute lung injury can be regulated via modulation of regulatory T cells and Th17 cells

Wang

Lin

et al. 2018

Scand J Immunol

View full text Add to dashboard Cite

Acute lung injury (ALI) is a severe inflammatory disease, for which no specific treatment exists. The decreased ratio of regulatory T cells (CD4+CD25+FoxP3 Tregs) and Th17 cells is implicated in ALI and inflammation. We here investigated whether maintaining the balance of CD4+CD25+Foxp3+Tregs and Th17 cells can alleviate lung injury. For CD4+CD25+FoxP3 Treg depletion, 200 μg of an anti‐CD25 antibody was administered intraperitoneally per mouse on days −3 and −1 before lipopolysaccharide (LPS) instillation. And 150 μg of TGF‐β was administered intraperitoneally per mouse on day 0 after LPS instillation. To down‐regulate of Th17 cells, 200 μg per mouse of isotype, IL‐17 or IL‐22 antibodies were injected intraperitoneally into mice at days 0 after LPS instillation. We detected lung morphology; lung wet‐to‐dry weight ratio; protein concentration, the count of total cells, neutrophils and macrophages, and cytokines in bronchoalveolar lavage fluid (BALF). And we also evaluated the percentage of CD4+CD25+Foxp3+Tregs in lung, and Th17 cells in lung. CD4+CD25+Foxp3+Tregs depletion via anti‐CD25 treatment or TGF‐β neutralization delayed recovery of ALI. The prolonged inflammation was mainly dominated by neutrophils, macrophages and Th17 cells. Furthermore, inhibition of Th17 cells via monoclonal antibodies against IL‐17 and IL‐22 alleviated ALI inflammation by inhibiting the recruitment of neutrophils and macrophages, increasing the number of CD4+CD25+Foxp3+Tregs. Our findings support a critical role for CD4+CD25+Foxp3+Tregs in regulating from ALI pathophysiology, and a potential therapeutic role for the inhibition of Th17 cells in ALI treatment. These findings provide a rationale for treating patients with ALI by modulating CD4+CD25+Foxp3+Tregs and Th17 cells.

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Recovery from acute lung injury can be regulated via modulation of regulatory T cells and Th17 cells

Wang

Lin

et al. 2018

Scand J Immunol

View full text Add to dashboard Cite

show abstract

“…Several studies have shown that speci c regulation of T cell differentiation could improve the immunity and in ammation state of ARDS in animal models, resulting in prognosis improvement 21,23,24 . It was also found in our study that the regulation of T cell differentiation in patients with community-acquired pneumonia was directly related to their prognosis 25 .…”

Section: Discussionmentioning

confidence: 99%

Overexpression of TGFβ1 in murine mesenchymal stem cells improves lung inflammation by impacting the Th17/Treg balance in LPS-induced ARDS mice

Chen

Zhang

Xie

et al. 2020

Preprint

View full text Add to dashboard Cite

Abstract Background: T helper 17 cells (Th17) /regulatory T cells (Treg), as subtypes of CD4 + T cells, play an important role in the inflammatory response of acute respiratory distress syndrome (ARDS). However, there is still a lack of effective methods to regulate the differentiation balance of Th17/Treg. It was proven that mesenchymal stem cells (MSCs) could regulate the differentiation of CD4 + T cells, but the mechanism is still unclear. TGFβ1, a paracrine cytokine of MSCs, could also regulate the differentiation of Th17/Treg but is lowly expressed in MSCs. Therefore, mouse MSCs (mMSCs) overexpressing TGFβ1 were constructed by lentivirus transfection and intratracheally transplanted into LPS-induced ARDS mice in our study. The aim of this study was to evaluate the therapeutic effects of mMSCs overexpressing TGFβ1 on inflammation and immunoregulation by impacting the Th17/Treg balance in LPS-induced ARDS mice. Methods: mMSCs overexpressing TGFβ1 were constructed using lentiviral vectors. Then, mouse bone-marrow-derived MSCs (mBM-MSC) and mBM-MSC-TGFβ1 (mBM-MSC overexpressing TGFβ1) were transplanted intratracheally into ARDS mice induced by lipopolysaccharide. At 3 d and 7 d after transplantation, the mice were sacrificed, and the homing of the mMSCs was assayed by ex vivo optical imaging. The relative numbers of Th17 and Treg in the lungs and spleens of mice were detected by FCM. IL-17A and IL-10 levels in the lungs of mice were analysed by western blot. Permeability and inflammatory cytokines were evaluated by analysing the protein concentration of BALF using ELISA. Histopathology of the lungs was assessed by haematoxylin and eosin staining and lung injury scoring. Alveolar lung fibrosis was assessed by Masson’s trichrome staining and Ashcroft scoring. The mortality of ARDS mice was followed until 7 days after transplantation. Results: The transduction efficiencies mediated by the lentiviral vectors ranged from 82.3-88.6%. Overexpressing TGF-β1 inhibited the proliferation of mMSCs during days 5-7 ( p <0.05) but had no effect on mMSCs differentiation or migration ( p >0.05). Compared to that in the LPS+mBM-MSC-NC group mice, engraftment of mMSCs overexpressing TGFβ1 led to much more differentiation of T cells into Th17 or Treg ( p <0.05), improved permeability of injured lungs ( p <0.05) and ameliorative histopathology of lung tissue in ARDS mice ( p <0.05). Moreover, IL-17A content was also decreased while IL-10 content was increased in the LPS+mBM-MSC-TGFβ1 group compared with those in the LPS+mBM-MSC-NC group ( p <0.05). Finally, mMSCs overexpressing TGFβ1 did not aggravate lung fibrosis in ARDS mice ( p >0.05). Conclusion: MSCs overexpressing TGFβ1 could regulate lung inflammation and attenuate lung injuries by modulating the imbalance of Th17/Treg in the lungs of ARDS mice.

show abstract

“…8). Several studies have veri ed that Treg/Th17 skewing plays a crucial role in ARDS (7,8,10,25,26). LPS, an endotoxin originating from the cell wall of gram-negative bacteria, was most used for a bacterial hyperin ammatory model of experimental ARDS (27).…”

Section: Effects Of Mir-155 Expression On Proliferation Capacity and mentioning

confidence: 99%

“…Excessive generation and activation of Th17 cells attribute to hyperin ammatory damage (9). Recent clinical studies among ARDS patients have identi ed a signi cantly closed link between increased Th17 frequency and greater illness severity and showed the levels of IL-17A were increased in bronchoalveolar lavage (10). Accordingly, Tregs, characterized by forkhead box P3(Foxp3) contribute to the resolution of hyperin ammatory response by regulating responses mediated by T helper cells.…”

mentioning

confidence: 99%

Mesenchymal Stem Cells-Secreted TGF-β1 Restores Treg/Th17 Skewing Induced by Lipopolysaccharide and Hypoxia Challenge via miR-155 Suppression

Xue

Zhang

Liu

et al. 2020

Preprint

View full text Add to dashboard Cite

Background: Regulatory T cells (Treg)/T helper (Th) 17 skewing plays a crucial role in development of acute respiratory distress (ARDS). Mesenchymal stem cells (MSCs)-secreted transforming growth factor (TGF)-β1 has remarkable immunomodulatory effects on CD4+T cells, being environment sensitive and remains lack of discussion in hypoxic and inflammatory condition of ARDS.Methods: Purified mice splenic CD4+ T cells were pre-coated with anti-CD3 (5ug/ml) and anti-CD28 (2ug/ml) overnight. RAW264.7 cells were added as antigen presenting cells (APCs). T cells with and without RAW264.7 cells were treated with various LPS concentrations of 0,10,100,1000ng/ml or/and at hypoxia condition of 5% O2. Based on LPS (100ng/ml) and hypoxia condition (5% O2) as stimuli, MSCs were set in direct coculture or indirect coculture methods by transwell system. Anti-TGF-β1 neutralization antibody was added to explore the role of TGF-β1 among the soluble factors secreted by MSCs; miR-155 overexpression of CD4+T cells were performed by transfection and then were added to the MSCs-CD4+T cells coculture system in hypoxic and LPS-stimulated condition. After 48 hours, cells or supernatant were collected for detection of frequency of Treg and Th17 subsets, CD4+T cells apoptosis and proliferation capacity assay by flowcytometry, secretions of INF-γ, IL-17A, IL-21, TGF-β1 and IL-10 by ELISA, levels of miR-155, Rorc, Foxp3 and Ptpn2 mRNA expression of CD4+T cells by RT-PCR.Results: MSCs could restore the skewed Treg/Th17 induced by LPS and hypoxia as compared to groups without MSCs with increased secretion of TGF-β1, IL-10 and IL-17A(P<0.05) and attenuate the increased expression of miR-155 in CD4+T cells, which was independent on cell-to-cell contact mechanism while TGF-β1 neutralization could significantly inhibit the effects of MSCs restoring the skewed Treg/Th17 and abolished its effect on miR-155 expression in CD4+T cells.Conclusions: These findings suggested miR-155 suppression of CD4+T cells mediated MSCs-secreted TGF-β1 modulating the skewed Treg/Th17 induced by LPS-hypoxia challenge, providing evidence when proposing future T lymphocyte-targeted cell therapy in ARDS.

show abstract

Resolution acute respiratory distress syndrome through reversing the imbalance of Treg/Th17 by targeting the cAMP signaling pathway

Cited by 27 publications

References 22 publications

Recovery from acute lung injury can be regulated via modulation of regulatory T cells and Th17 cells

Recovery from acute lung injury can be regulated via modulation of regulatory T cells and Th17 cells

Overexpression of TGFβ1 in murine mesenchymal stem cells improves lung inflammation by impacting the Th17/Treg balance in LPS-induced ARDS mice

Mesenchymal Stem Cells-Secreted TGF-β1 Restores Treg/Th17 Skewing Induced by Lipopolysaccharide and Hypoxia Challenge via miR-155 Suppression

Contact Info

Product

Resources

About