TGF-\u03b21/IL-11/MEK/ERK signaling mediates senescence-associated pulmonary fibrosis in a stress-induced premature senescence model of Bmi-1 deficiency

Haiyun Chen,Qing Li,Xianhui Lv,Dengshun Miao,Rong Wang,Hongjie Chen,Xin Gu,Jiawen Zhou,Zhiyuan Mao,Chunfeng Xie,Jialong Liang,Guoping Zuo,Haijian Sun,Jianliang Jin

doi:10.1038/s12276-019-0371-7

Abstract

To study whether TGF-β1/IL-11/MEK/ERK (TIME) signaling mediates senescence-associated pulmonary fibrosis (SAPF) in Bmi-1-deficient (Bmi-1−/−) mice and determines the major downstream mediator of Bmi-1 and crosstalk between p16INK4a and reactive oxygen species that regulates SAPF, phenotypes were compared among 7-week-old p16INK4a and Bmi-1 double-knockout, N-acetylcysteine (NAC)-treated Bmi-1−/−, Bmi-1−/−, and wild-type mice. Pulmonary fibroblasts and alveolar type II epithelial (AT2) cells were used for experiments. Human pulmonary tissues were tested for type Ι collagen, α-smooth muscle actin (α-SMA), p16INK4a, p53, p21, and TIME signaling by using enzyme-linked immunosorbent assay (ELISA). Our results demonstrated that Bmi-1 deficiency resulted in a shortened lifespan, ventilatory resistance, poor ventilatory compliance, and SAPF, including cell senescence, DNA damage, a senescence-associated secretory phenotype and collagen overdeposition that was mediated by the upregulation of TIME signaling. The signaling stimulated cell senescence, senescence-related secretion of TGF-β1 and IL-11 and production of collagen 1 by pulmonary fibroblasts and the epithelial-to-mesenchymal transition of AT2 cells. These processes were inhibited by anti-IL-11 or the MEK inhibitor PD98059. NAC treatment prolonged the lifespan and ameliorated pulmonary dysfunction and SAPF by downregulating TIME signaling more than p16INK4a deletion by inhibiting oxidative stress and DNA damage and promoting ubiquitin-proteasome degradation of p16INK4a and p53. Cytoplasmic p16INK4a accumulation upregulated MEK/ERK signaling by inhibiting the translocation of pERK1/2 (Thr202/Tyr204) from the cytoplasm to the nucleus in senescent fibroblasts. The accumulation of collagen 1 and α-SMA in human lungs accompanied by cell senescence may be mediated by TIME signaling. Thus, this signaling in aging fibroblasts or AT2 cells could be a therapeutic target for preventing SAPF.

Highlights

Aging drives idiopathic pulmonary fibrosis (IPF) and non-IPF lung fibrotic disorders, which are characterized by chronic activation of profibrotic factors and pulmonaryThe senescence-associated secretory phenotype (SASP) turns senescent fibroblasts into proinflammatory cells that induces senescence and the epithelial-to-mesenchymal transition (EMT) of nearby epithelial cells[3,4,5]
This study demonstrated that in a stressinduced premature senescence (SIPS) model of Bmi-1 deficiency, upregulated TIME signals contributed to senescence-associated pulmonary fibrosis (SAPF) and dysfunction by promoting cell senescence and stimulating TGF-β1 and IL-11 secretion and collagen 1 production in aging pulmonary fibroblasts and the EMT in aging AT2 cells (Fig. 8d)
This study evaluated pulmonary functional and histological alterations to determine if Bmi-1-deficient mice showed senescenceassociated fibrosing interstitial pneumonia

Summary

Introduction

Aging drives idiopathic pulmonary fibrosis (IPF) and non-IPF lung fibrotic disorders, which are characterized by chronic activation of profibrotic factors and pulmonaryThe senescence-associated secretory phenotype (SASP) turns senescent fibroblasts into proinflammatory cells that induces senescence and the epithelial-to-mesenchymal transition (EMT) of nearby epithelial cells[3,4,5]. Inhibition of cell senescence and TIME signals in pulmonary fibroblasts by NAC in Bmi-1−/− vs Bmi-1−/−p16−/− mice To investigate whether p16 inhibited translocation of pERK1/2 (Thr202/Tyr204) from the cytoplasm to nucleus, pulmonary fibroblasts from WT mice were treated with TGF-β1 and proteins were extracted for p16 or Bmi-1 coimmunoprecipitation analysis.

Results

Conclusion