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The Th1/Th17 balance dictates the fibrosis response in murine radiation-induced lung disease.

ABSTRACT: Radiotherapy can result in lung diseases pneumonitis or fibrosis dependent on patient susceptibility. Herein we used inbred and genetically altered mice to investigate whether the tissue adaptive immune response to radiation injury influences the development of radiation-induced lung disease. Six inbred mouse strains were exposed to 18?Gy whole thorax irradiation and upon respiratory distress strains prone to pneumonitis with fibrosis presented an increased pulmonary frequency of Thelper (Th)17 cells which was not evident in strains prone solely to pneumonitis. The contribution of Th17 cells to fibrosis development was supported as the known enhanced fibrosis of toll-like receptor 2&4 deficient mice, compared to C57BL/6J mice, occurred with earlier onset neutrophilia, and with increased levels of pulmonary Th17, but not Th1, cells following irradiation. Irradiated Il17-/- mice lacked Th17 cells, and were spared both fibrosis and pneumonitis, as they survived to the end of the experiment with a significantly increased pulmonary Th1 cell frequency, only. Interferon-?-/- mice, deficient in Th1 cells, developed a significantly enhanced fibrosis response compared to that of C57BL/6J mice. The tissue adaptive immune response influences the pulmonary disease response to radiotherapy, as an increased Th17 cell frequency enhanced and a Th1 response spared, fibrosis in mice.

SUBMITTER: Paun A

PROVIDER: S-EPMC5599556 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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The Th1/Th17 balance dictates the fibrosis response in murine radiation-induced lung disease.

Paun Alexandra A Bergeron Marie-Eve ME Haston Christina K CK

Scientific reports 20170914 1

Radiotherapy can result in lung diseases pneumonitis or fibrosis dependent on patient susceptibility. Herein we used inbred and genetically altered mice to investigate whether the tissue adaptive immune response to radiation injury influences the development of radiation-induced lung disease. Six inbred mouse strains were exposed to 18 Gy whole thorax irradiation and upon respiratory distress strains prone to pneumonitis with fibrosis presented an increased pulmonary frequency of Thelper (Th)17 ...[more]

PMID: 28912510

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Project description:BackgroundT 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 transduction 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.MethodsmMSCs 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 and 7 days 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.ResultsThe transduction efficiencies mediated by the lentiviral vectors ranged from 82.3 to 88.6%. Overexpressing TGFβ1 inhibited the proliferation of mMSCs during days 5-7 (p < 0.05) but had no effect on mMSC 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).ConclusionMSCs overexpressing TGFβ1 could regulate lung inflammation and attenuate lung injuries by modulating the imbalance of Th17/Treg in the lungs of ARDS mice.

Project description:BackgroundRadiotherapy is the main treatment modality for thoracic tumours, but it may induce pulmonary fibrosis. Currently, the pathogenesis of radiation-induced pulmonary fibrosis (RIPF) is unclear, and effective treatments are lacking. Transforming growth factor beta 1 (TGFβ1) plays a central role in RIPF. We found that activated TGFβ1 had better performance for radiation pneumonitis (RP) risk prediction by detecting activated and total TGFβ1 levels in patient serum. αv integrin plays key roles in TGFβ1 activation, but the role of αv integrin-mediated TGFβ1 activation in RIPF is unclear. Here, we investigated the role of αv integrin-mediated TGFβ1 activation in RIPF and the application of the integrin antagonist cilengitide to prevent RIPF.MethodsItgavloxP/loxP ;Pdgfrb-Cre mice were generated by conditionally knocking out Itgav in myofibroblasts, and wild-type mice were treated with cilengitide or placebo. All mice received 16 Gy of radiation or underwent a sham radiation procedure. Lung fibrosis was measured by a modified Ashcroft score and microcomputed tomography (CT). An enzyme-linked immunosorbent assay (ELISA) was used to measure the serum TGFβ1 concentration, and total Smad2/3 and p-Smad2/3 levels were determined via Western blotting.ResultsConditional Itgav knockout significantly attenuated RIPF (p < .01). Hounsfield units (HUs) in the lungs were reduced in the knockout mice compared with the control mice (p < .001). Conditional Itgav knockout decreased active TGFβ1 secretion and inhibited fibroblast p-Smad2/3 expression. Exogenous active TGFβ1, but not latent TGFβ1, reversed these reductions. Furthermore, cilengitide treatment elicited similar results and prevented RIPF.ConclusionsThe present study revealed that conditional Itgav knockout and cilengitide treatment both significantly attenuated RIPF in mice by inhibiting αv integrin-mediated TGFβ1 activation.HighlightsActivated TGFβ1 has a superior capacity in predicting radiation pneumonitis (RP) risk and plays a vital role in the development of radiation-induced pulmonary fibrosis (RIPF). Conditional knock out Itgav in myofibroblasts prevented mice from developing RIPF. Cilengitide alleviated the development of RIPF by inhibiting αv integrin-mediated TGFβ1 activation and may be used in targeted approaches for preventing RIPF.

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The Th1/Th17 balance dictates the fibrosis response in murine radiation-induced lung disease.

Publications

The Th1/Th17 balance dictates the fibrosis response in murine radiation-induced lung disease.

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