Prolonged activation of IL-5–producing ILC2 causes pulmonary arterial hypertrophy

Ikutani, Masashi; Tsuneyama, Koichi; Kikuchi, Makoto; Fukuoka, Junya; Kudo, Fujimi; Nakae, Susumu; Arita, Makoto; Nagai, Yoshinori; Takaki, Satoshi; Takatsu, Kiyoshi

doi:10.1172/jci.insight.90721

Cited by 21 publications

(18 citation statements)

References 53 publications

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“…However, given the complexity of the effects of CGRP and NMU, much is still to be learned about the consequences of blocking these neuropeptides to various immune responses and disorders characterized by dysregulated inflammatory cytokines. The action of CGRP to tilt the balance between IL-5 and IL-13 will become quite consequential in situations such as pulmonary arterial hypertrophy in which IL-5-producing ILC2 and eosinophils play pivotal roles (Ikutani et al, 2017) or tissue fibrosis in which IL-13 is an important driver (Gieseck et al, 2018). Understanding the contribution of ILCs, their effector cytokines, and the role of CGRP in tissue damage and repair is clearly an important area for future research.…”

Section: Discussionmentioning

confidence: 99%

Neuropeptide CGRP Limits Group 2 Innate Lymphoid Cell Responses and Constrains Type 2 Inflammation

Nagashima¹,

Mahlakõiv²,

Shih³

et al. 2019

Immunity

211

176

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Section: Discussionmentioning

confidence: 99%

Neuropeptide CGRP Limits Group 2 Innate Lymphoid Cell Responses and Constrains Type 2 Inflammation

Nagashima¹,

Mahlakõiv²,

Shih³

et al. 2019

Immunity

211

176

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show abstract

“…observed that the large vessels and cardiac microvascular endothelial cells were the major sources expressing IL-33 and ST2 [ 27 ], suggesting that, in vitro , exogenous human IL-33 acts on vascular endothelial cells, but not cardiomyocytes, fibroblasts or vascular smooth muscle cells, at least in terms of eliciting production of other proinflammatory cytokines. A very recent study has reported that administration of IL-33 over a prolonged period results in the development of pulmonary arterial hypertrophy [ 28 ]. Our data showed that co-culture of vascular endothelial cells with smooth muscle cells significantly enhanced proliferation of the latter, an effect further enhanced in the presence of additional IL-33, while IL-33 alone exerted no such effect.…”

Section: Discussionmentioning

confidence: 99%

IL-33 Initiates Vascular Remodelling in Hypoxic Pulmonary Hypertension by up-Regulating HIF-1α and VEGF Expression in Vascular Endothelial Cells

Liu¹,

Wang²,

Wang³

et al. 2018

EBioMedicine

127

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IL-33 may play a role in the vascular remodelling of hypoxic pulmonary hypertension (PH) but the precise mechanisms are still unclear. We hypothesized that hypoxia promotes expression of IL-33 and its receptor ST2 on vascular endothelial cells, which in turn leads to dysfunction of vascular endothelial cells and smooth muscle cells contributing to PH. Immunohistochemistry showed that immunoreactivity for IL-33 and ST2 was significantly increased in lung tissue of murine model of hypoxia-induced PH (HPH) and of subjects with bronchiectasis-PH. trans-Thoracic echocardiography showed that haemodynamic changes and right ventricular hypertrophy associated with HPH were significantly abrogated in St2−/− compared with WT mice. Administration of IL-33 further exacerbated these changes in the hypoxia-exposed WT mice. In vitro, hypoxia significantly increased IL-33/ST2 expression by human pulmonary arterial endothelial cells (HPAECs), while exogenous IL-33 enhanced proliferation, adhesiveness and spontaneous angiogenesis of HPAECs. Knockdown of endogenous Il33 or St2 using siRNA transfection significantly suppressed these effects in both normoxic and hypoxic culture-conditions. Deletion of the St2 gene attenuated hypoxia-induced, elevated lung expression of HIF-1α/VEGFA/VEGFR-2/ICAM-1, while administration of exogenous VEGFA partially reversed the attenuation of the haemodynamic indices of PH. Correspondingly, knockdown of the St2 or Hif1α genes almost completely abrogated IL-33-induced expression of HIF-1α/VEGFA/VEGFR-2 by HPAECs in vitro. Further, IL-33-induced angiogenesis by HPAECs was extensively abrogated by knockdown of the Hif1α/Vegfa or Vegfr2 genes. These data suggest that hypoxia induces elevated expression of IL-33/ST2 by HPAECs which, at least partly by increasing downstream expression of HIF-1α and VEGF initiates vascular remodelling resulting in HPH.

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“…Several in vivo mouse studies suggest that IL-33 plays an important role in pulmonary vascular remodeling during chronic airway inflammation. Long-term IL-33 airway administration induces pulmonary arterial hypertrophy in mice that is dependent on IL-5-producing ILC2s and eosinophils (84). It is unknown whether the direct action of IL-33 on endothelial cells contributes to development of pulmonary arterial hypertrophy in this model.…”

Section: Il-33 and Endothelial Cells In The Lungmentioning

confidence: 94%

Contributions of IL-33 in Non-hematopoietic Lung Cells to Obstructive Lung Disease

Drake

Prakash

2020

Front. Immunol.

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Interleukin (IL)-33 plays important roles in pulmonary immune responses and lung diseases including asthma and chronic obstructive pulmonary disease (COPD). There is substantial interest in identifying and characterizing cellular sources vs. targets of IL-33, and downstream signaling pathways involved in disease pathophysiology. While epithelial and immune cells have largely been the focus, in this review, we summarize current knowledge of expression, induction, and function of IL-33 and its receptor ST2 in non-hematopoietic lung cells in the context of health and disease. Under basal conditions, epithelial cells and endothelial cells are thought to be the primary resident cell types that express high levels of IL-33 and serve as ligand sources compared to mesenchymal cells (smooth muscle cells and fibroblasts). Under inflammatory conditions, IL-33 expression is increased in most non-hematopoietic lung cells, including epithelial, endothelial, and mesenchymal cells. In comparison to its ligand, the receptor ST2 shows low expression levels at baseline but similar to IL-33, ST2 expression is upregulated by inflammation in these non-hematopoietic lung cells which may then participate in chronic inflammation both as sources and autocrine/paracrine targets of IL-33. Downstream effects of IL-33 may occur via direct receptor activation or indirect interactions with the immune system, overall contributing to lung inflammation, airway hyper-responsiveness and remodeling (proliferation and fibrosis). Accordingly from a therapeutic perspective, targeting IL-33 and/or its receptor in non-hematopoietic lung cells becomes relevant.

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Prolonged activation of IL-5–producing ILC2 causes pulmonary arterial hypertrophy

Cited by 21 publications

References 53 publications

Neuropeptide CGRP Limits Group 2 Innate Lymphoid Cell Responses and Constrains Type 2 Inflammation

Neuropeptide CGRP Limits Group 2 Innate Lymphoid Cell Responses and Constrains Type 2 Inflammation

IL-33 Initiates Vascular Remodelling in Hypoxic Pulmonary Hypertension by up-Regulating HIF-1α and VEGF Expression in Vascular Endothelial Cells

Contributions of IL-33 in Non-hematopoietic Lung Cells to Obstructive Lung Disease

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