Role of IL-11 in vascular function of pulmonary fibrosis patients

Roger, Inés; Estornut, Cristina; Ballester, Beatriz; Milara, Javier; Cortijo, Julio

doi:10.1183/13993003.congress-2019.pa1424

Cited by 5 publications

(8 citation statements)

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“…Hence, inhibition of IL11 signaling, which is predicted to have a favorable safety profile 57 , may be beneficial in aortic disease. IL11 was recently found to be increased in pulmonary arterial VSMCs from patients with pulmonary arterial hypertension 58 and IL11 may be more generally important for diseases characterized by VSMC dysfunction, which requires further study.…”

Section: Discussionmentioning

confidence: 99%

Interleukin-11 is important for vascular smooth muscle phenotypic switching and aortic inflammation, fibrosis and remodeling in mouse models

Lim

Corden

et al. 2020

Sci Rep

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Transforming growth factor beta-1 (TGFβ1) is a major driver of vascular smooth muscle cell (VSMC) phenotypic switching, an important pathobiology in arterial disease. We performed RNA-sequencing of TGFβ1-stimulated human aortic or arterial VSMCs which revealed large and consistent upregulation of Interleukin 11 (IL11). IL11 has an unknown function in VSMCs, which highly express the IL11 receptor alpha, suggestive of an autocrine loop. In vitro, IL11 activated ERK signaling, but inhibited STAT3 activity, and caused VSMC phenotypic switching to a similar extent as TGFβ1 or angiotensin II (ANGII) stimulation. Genetic or therapeutic inhibition of IL11 signaling reduced TGFβ1- or ANGII-induced VSMC phenotypic switching, placing IL11 activity downstream of these factors. Aortas of mice with Myh11-driven IL11 expression were remodeled and had reduced contractile but increased matrix and inflammatory genes expression. In two models of arterial pressure loading, IL11 was upregulated in the aorta and neutralizing IL11 antibodies reduced remodeling along with matrix and pro-inflammatory gene expression. These data show that IL11 plays an important role in VSMC phenotype switching, vascular inflammation and aortic pathobiology.

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Section: Discussionmentioning

confidence: 99%

Interleukin-11 is important for vascular smooth muscle phenotypic switching and aortic inflammation, fibrosis and remodeling in mouse models

Lim

Corden

et al. 2020

Sci Rep

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“…Invasive IPF fibroblasts have been shown to secrete high levels of IL-11 57 . IPF patients with pulmonary hypertension (PH) have an even greater elevation in IL-11 and IL11RA expression in the lungs, which is associated with increased pulmonary artery remodeling compared to that of IPF patients without PH or non-IPF individuals 58 .…”

Section: Stromal and Parenchymal Il-11 Secretion Is A Hallmark Of Infmentioning

confidence: 99%

Interleukin-11 signaling underlies fibrosis, parenchymal dysfunction, and chronic inflammation of the airway

Cook

Schäfer

2020

Exp Mol Med

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Interleukin (IL)-11 evolved as part of the innate immune response. In the human lung, IL-11 upregulation has been associated with viral infections and a range of fibroinflammatory diseases, including idiopathic pulmonary fibrosis. Transforming growth factor-beta (TGFβ) and other disease factors can initiate an autocrine loop of IL-11 signaling in pulmonary fibroblasts, which, in a largely ERK-dependent manner, triggers the translation of profibrotic proteins. Lung epithelial cells also express the IL-11 receptor and transition into a mesenchymal-like state in response to IL-11 exposure. In mice, therapeutic targeting of IL-11 with antibodies can arrest and reverse bleomycin-induced pulmonary fibrosis and inflammation. Intriguingly, fibroblast-specific blockade of IL-11 signaling has anti-inflammatory effects, which suggests that lung inflammation is sustained, in part, through IL-11 activity in the stroma. Proinflammatory fibroblasts and their interaction with the damaged epithelium may represent an important but overlooked driver of lung disease. Initially thought of as a protective cytokine, IL-11 is now increasingly recognized as an important determinant of lung fibrosis, inflammation, and epithelial dysfunction.

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“…Many previous studies have described the important role that interleukins of the IL-6 family play in the pathogenesis of PH, among which IL-6 and IL-11 are the most relevant. The first demonstration of increased IL-6 dates to 1996 [ 25 ]; however, the involvement of IL-11 in PH was recently demonstrated by our group [ 26 ]. The formation of a hexameric complex of IL-6/IL-6Rα/GP130 or IL-11/IL-11Rα/GP130 is required for IL-6 or IL-11 signaling, respectively.…”

Section: Jak/stat Activatorsmentioning

confidence: 99%

“…In the lungs, IL-11Rα is highly expressed in cells such as fibroblasts, vascular smooth muscle cells, and epithelial cells [ 33 , 34 , 35 ]. We have recently described that IPF patients with PH have a greater elevation of IL-11 and IL11-Rα expression in pulmonary arteries, which is associated with pulmonary artery remodeling [ 26 ].…”

Section: Jak/stat Activatorsmentioning

confidence: 99%

The Role of JAK/STAT Molecular Pathway in Vascular Remodeling Associated with Pulmonary Hypertension

Roger

Milara

Montero

et al. 2021

IJMS

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Pulmonary hypertension is defined as a group of diseases characterized by a progressive increase in pulmonary vascular resistance (PVR), which leads to right ventricular failure and premature death. There are multiple clinical manifestations that can be grouped into five different types. Pulmonary artery remodeling is a common feature in pulmonary hypertension (PH) characterized by endothelial dysfunction and smooth muscle pulmonary artery cell proliferation. The current treatments for PH are limited to vasodilatory agents that do not stop the progression of the disease. Therefore, there is a need for new agents that inhibit pulmonary artery remodeling targeting the main genetic, molecular, and cellular processes involved in PH. Chronic inflammation contributes to pulmonary artery remodeling and PH, among other vascular disorders, and many inflammatory mediators signal through the JAK/STAT pathway. Recent evidence indicates that the JAK/STAT pathway is overactivated in the pulmonary arteries of patients with PH of different types. In addition, different profibrotic cytokines such as IL-6, IL-13, and IL-11 and growth factors such as PDGF, VEGF, and TGFβ1 are activators of the JAK/STAT pathway and inducers of pulmonary remodeling, thus participating in the development of PH. The understanding of the participation and modulation of the JAK/STAT pathway in PH could be an attractive strategy for developing future treatments. There have been no studies to date focused on the JAK/STAT pathway and PH. In this review, we focus on the analysis of the expression and distribution of different JAK/STAT isoforms in the pulmonary arteries of patients with different types of PH. Furthermore, molecular canonical and noncanonical JAK/STAT pathway transactivation will be discussed in the context of vascular remodeling and PH. The consequences of JAK/STAT activation for endothelial cells and pulmonary artery smooth muscle cells’ proliferation, migration, senescence, and transformation into mesenchymal/myofibroblast cells will be described and discussed, together with different promising drugs targeting the JAK/STAT pathway in vitro and in vivo.

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Role of IL-11 in vascular function of pulmonary fibrosis patients

Cited by 5 publications

References 0 publications

Interleukin-11 is important for vascular smooth muscle phenotypic switching and aortic inflammation, fibrosis and remodeling in mouse models

Interleukin-11 is important for vascular smooth muscle phenotypic switching and aortic inflammation, fibrosis and remodeling in mouse models

Interleukin-11 signaling underlies fibrosis, parenchymal dysfunction, and chronic inflammation of the airway

The Role of JAK/STAT Molecular Pathway in Vascular Remodeling Associated with Pulmonary Hypertension

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