IL-25 induces airways angiogenesis and expression of multiple angiogenic factors in a murine asthma model

Abstract

Background: Th2-promoting cytokine IL-25 might contribute to bronchial mucosal vascular remodelling in asthma through its receptor expressed by vascular endothelial and vascular smooth muscle cells. Methods: By utilising a newly established chronic asthma murine model induced by direct exposure of the airways to IL-25 alone, we examined effects of IL-25 on angiogenesis, vascular remodelling and expression of angiogenic factors, compared changes with those in a "classical" ovalbumin (OVA)-induced murine asthma model. IL-25 and OVA were intranasally instilled into the airways of BALB/c mice for up to 55 days. Airways vessels and angiogenic factors, including Von Willebrand Factor (vWF), amphiregulin, angiogenin, endothelin-1, transcription factor ERG, basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), insulin-like growth factor (IGF-1) and vascular endothelial growth factor (VEGF) in lung sections, homogenates and BAL fluid were detected and quantified by immunostaining or enzyme linked immunosorbent assay (ELISA). An in house assay was also utilised to compare the effects of IL-25 and other Th2-cytokines on angiogenesis by human vascular endothelial cells. Results: Repetitive intranasal challenge with IL-25 alone or OVA alone in OVA-presensitised animals significantly increased peribronchial vWF + vessels in the murine airways, which was associated with remarkably elevated expression of amphiregulin, angiogenin, endothelin-1, bFGF, EGF, IGF-1, VEGF and ERG. IL-25, but not Th-2-cytokines induced human angiogenesis in vitro. Conclusions: The data suggest that chronic exposure of murine airways to IL-25 alone is able to reproduce a local angiogenic milieu. Thus, blocking IL-25 may attenuate vascular remodelling and improve outcomes in asthma patients.

The Identification of Childhood Asthma Progression-Related lncRNAs and mRNAs Suitable as Biomarkers Using Weighted Gene Coexpression Network Analysis

“…VWF , a large plasma glycoprotein, plays a vital role in mediating the balance between blood clotting and bleeding [ 36 ]. A study by Yao et al [ 37 ] showed that VWF was highly expressed in an IL-25-induced murine asthma model and was associated with bronchial mucosal vascular remodeling in asthma. LAMB3 and LAMA4 belong to the laminin subunit family and have been reported to be involved in the metastasis and invasion of some types of cancer [ 38 , 39 ].…”

Interleukin (IL)‐25: Pleiotropic roles in asthma

“…Likewise, a chronic murine model established in our laboratory demonstrated that intranasal exposure to IL‐25 up to 2 months mimicked OVA‐induced or house dust mite‐induced asthma‐like changes . Interestingly, this model manifested asthma‐like but allergen‐independent acute and chronic inflammation and structural changes of remodelling in the airways, including eosinophilia, predominant expression of Th2‐type cytokines, AHR, goblet cell hyperplasia, sub‐epithelial collagen deposition, smooth muscle hyperplasia/hypertrophy and angiogenesis . However, although IL‐25 can directly induce the proliferation and expression of collagen I/III and smooth muscle alpha‐actin by primary human lung fibroblasts and can induce angiogenesis in vitro by directly acting on HUVECs we still cannot exclude the indirect role of IL‐25 on fibrosis and angiogenesis of asthmatic airways by affecting the expression of Th2 cytokines originated from other immune cells.…”

“…61 Interestingly, this model manifested asthma-like but allergen-independent acute and chronic inflammation and structural changes of remodelling in the airways, including eosinophilia, predominant expression of Th2-type cytokines, AHR, goblet cell hyperplasia, subepithelial collagen deposition, smooth muscle hyperplasia/hypertrophy and angiogenesis. [61][62][63] However, although IL-25 can directly induce the proliferation and expression of collagen I/III and smooth muscle alpha-actin by primary human lung fibroblasts and can induce angiogenesis in vitro by directly acting on HUVECs we still cannot exclude the indirect role of IL-25 on fibrosis and angiogenesis of asthmatic airways by affecting the expression of Th2 cytokines originated from other immune cells. Nevertheless, the above-mentioned and other in vivo animal studies, using overexpression or depletion methods, provide solid evidence supporting a critical role of IL-25 in the development of airway inflammation and remodelling of asthma.…”

IL‐25 protects against high‐fat diet‐induced hepatic steatosis in mice by inducing IL‐25 and M2a macrophage production

“…35 Yao et al demonstrated that the chronic exposure of murine airways to IL-25 alone is able to increase reproduction of a local angiogenic milieu, as well as cause functional airway remodeling. 36,37 Numerous studies have demonstrated solid evidence in support of a critical role of IL-25 in the development of airway inflammation and asthma remodeling. 38,39 Studies in mouse models have also shown that IL-25 and type 2 innate lymphoid cells can result in the induction of pulmonary fibrosis.…”