NLRP3 Inflammasome Activation Contributes to Mechanical Stretch–Induced Endothelial-Mesenchymal Transition and Pulmonary Fibrosis

Zhou, Lv; Wang, Yan; Liu, Yujian; Mao, Yanfei; Dong, Wenwen; Ding, Zhong-Nuo; Meng, Guangxun; Jiang, Lai; Zhu, Xiaoyan

doi:10.1097/ccm.0000000000002799

Cited by 77 publications

(59 citation statements)

References 39 publications

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“…IPF is a progressive, chronic, and ultimately fatal interstitial lung disease characterized by enhanced extracellular matrix deposition. Although the exact etiology in IPF is unclear, complex, and probably diverse, previous studies have identified EndoMT as one of the important processes for the establishment and progression of the fibrotic changes . In our study, we also found that all control groups showed no abnormalities, while WT‐BLM mice showed significant fibrotic responses in the lung; these were accompanied by decreased endothelial markers VE‐cadherin and CD31 but increased mesenchymal cell marker α‐smooth muscle actin (α‐SMA), indicating EndoMT.…”

Section: Discussionsupporting

confidence: 70%

“…Although the exact etiology in IPF is unclear, complex, and probably diverse, previous studies have identified EndoMT as one of the important processes for the establishment and progression of the fibrotic changes. [20][21][22] In our study, we also found that all control groups showed no abnormalities, while WT-BLM mice showed significant fibrotic responses in the lung; these were accompanied by decreased endothelial markers VE-cadherin and CD31 but increased mesenchymal cell marker α-smooth muscle actin (α-SMA), indicating EndoMT. Recent studies have demonstrated that myofibroblasts are the cells ultimately responsible for the severe organ fibrotic process such as in pulmonary fibrosis.…”

Section: Discussionmentioning

confidence: 67%

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SHIP‐1, a target of miR‐155, regulates endothelial cell responses in lung fibrosis

Tang

Mao

et al. 2019

FASEB j.

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Src Homology 2‐containing Inositol Phosphatase‐1 (SHIP‐1) is a target of miR‐155, a pro‐inflammatory factor. Deletion of the SHIP‐1 gene in mice caused spontaneous lung inflammation and fibrosis. However, the role and function of endothelial miR‐155 and SHIP‐1 in lung fibrosis remain unknown. Using whole‐body miR‐155 knockout mice and endothelial cell–specific conditional miR‐155 (VEC‐Cre‐miR‐155 or VEC‐miR‐155) or SHIP‐1 (VEC‐SHIP‐1) knockout mice, we assessed endothelial‐mesenchymal transition (EndoMT) and fibrotic responses in bleomycin (BLM) induced lung fibrosis models. Primary mouse lung endothelial cells (MLEC) and human umbilical vein endothelial cells (HUVEC) with SHIP‐1 knockdown were analyzed in TGF‐β1 or BLM, respectively, induced fibrotic responses. Fibrosis and EndoMT were significantly reduced in miR‐155KO mice and changes in EndoMT markers in MLEC after TGF‐β1 stimulation confirmed the in vivo findings. Furthermore, lung fibrosis and EndoMT responses were reduced in VEC‐miR‐155 mice but significantly enhanced in VEC‐SHIP‐1 mice after BLM challenge. SHIP‐1 knockdown in HUVEC cells resulted in enhanced EndoMT induced by BLM. Meanwhile, these changes involved the PI3K/AKT, JAK/STAT3, and SMAD/STAT signaling pathways. These studies demonstrate that endothelial miR‐155 plays an important role in fibrotic responses in the lung through EndoMT. Endothelial SHIP‐1 is essential in controlling fibrotic responses and SHIP‐1 is a target of miR‐155. Endothelial cells are an integral part in lung fibrosis.

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Section: Discussionsupporting

confidence: 70%

Section: Discussionmentioning

confidence: 67%

SHIP‐1, a target of miR‐155, regulates endothelial cell responses in lung fibrosis

Tang

Mao

et al. 2019

FASEB j.

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“…Excessive stretch can also lead to production of ROS which enhances EndMT by oxidative stress, [109,129] and TGF-β upregulation by NLRP3 inflammasome activation. [130] …”

Section: Applications Of Vascular Mechanobiologymentioning

confidence: 99%

Endothelial Cell Mechanotransduction in the Dynamic Vascular Environment

2018

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The vascular endothelial cells (ECs) that line the inner layer of blood vessels are responsible for maintaining vascular homeostasis under physiological conditions. In the presence of disease or injury, ECs can become dysfunctional and contribute to a progressive decline in vascular health. ECs are constantly exposed to a variety of dynamic mechanical stimuli, including hemodynamic shear stress, pulsatile stretch, and passive signaling cues derived from the extracellular matrix. This review describes the molecular mechanisms by which ECs perceive and interpret these mechanical signals. The translational applications of mechanosensing are then discussed in the context of endothelial-to-mesenchymal transition and engineering of vascular grafts.

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“…This link is exemplified in inflammatory lung injury diseases like VILI where mechanical ventilation exerts mechanical stress. Ventilator‐induced cyclic stretch of alveolar macrophages activates the macrophage NLRP3 inflammasome, and also in lung endothelial cells, to produce IL‐1β. Mechanotransduction modulates the macrophage inflammatory response in other systems as well .…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, mechanosensitive inflammasome activation has been implicated in acute respiratory distress syndrome (ARDS) pathophysiology. In a model of VILI, mechanical stress, induced by mechanical ventilation, activated the NLRP3 inflammasome in macrophages and endothelial cells, contributing to lung damage . Similarly, actin depolymerization induced by the mechanical stimulus of cyclic stretch also enhanced NLRP3 activation in tenocytes and consequently promoted tendinitis progression .…”

Section: Introductionmentioning

confidence: 99%

Cells under stress: The mechanical environment shapes inflammasome responses to danger signals

Joshi

Morley

2019

Journal of Leukocyte Biology

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Many intracellular signals, such as host danger-associated molecules and bacterial toxins during infection, elicit inflammasome activation. However, the mechanical environment in tissues may also influence the sensitivity of various inflammasomes to activation. The cellular mechanical environment is determined by the extracellular tissue stiffness, or its inverse, tissue compliance. Tissue stiffness is sensed by the intracellular cytoskeleton through a process termed mechanotransduction. Thus, extracellular compliance and the intracellular cytoskeleton may regulate the sensitivity of inflammasome activation. Control of proinflammatory signaling by tissue compliance may contribute to the pathogenesis of diseases such as ventilator-induced lung injury during bacterial pneumonia and tissue fibrosis in inflammatory disorders. The responsible signaling cascades in inflammasome activation pathways and mechanotransduction crosstalk are not yet fully understood. This rather different immunomodulatory perspective will be reviewed and open questions discussed here. K E Y W O R D S cell adhesion, inflammasome, inflammation, integrins, mechanobiology, monocytes/macrophages

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NLRP3 Inflammasome Activation Contributes to Mechanical Stretch–Induced Endothelial-Mesenchymal Transition and Pulmonary Fibrosis

Cited by 77 publications

References 39 publications

SHIP‐1, a target of miR‐155, regulates endothelial cell responses in lung fibrosis

SHIP‐1, a target of miR‐155, regulates endothelial cell responses in lung fibrosis

Endothelial Cell Mechanotransduction in the Dynamic Vascular Environment

Cells under stress: The mechanical environment shapes inflammasome responses to danger signals

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