Interleukin-25 Induces Pulmonary Arterial Remodeling via Natural Killer T Cell-Dependent Mechanisms

Abstract

Background: Recent studies have shown that prolonged Th2-type immune inflammation in the lung induces pulmonary arterial remodeling, in part through the induction of resistin-like molecule α (RELMα) expression. However, the role of interleukin-25 (IL-25; which promotes this inflammation) in the development of the pulmonary arterial remodeling remains unknown. Methods: Ovalbumin (OVA)-sensitized C57BL/6 mice were challenged with OVA inhalation 3 times a week for 3 weeks. The effects of neutralizing anti-IL-25 antibody on OVA-induced pulmonary arterial remodeling and RELMα expression in the lung were examined. The pulmonary arterial remodeling and RELMα expression in the lung were examined in lung-specific IL-25 transgenic mice (CC10 IL-25 mice) and CC10 IL-25 mice in a natural killer T (NKT) cell-deficient background (CC10 IL-25 NKT^-/- mice). Results: Repeated OVA inhalation induced pulmonary arterial wall thickening and the expression of IL-25 and RELMα mRNA in the lung in OVA-sensitized mice. Injection of neutralizing anti-IL-25 antibody inhibited OVA-induced pulmonary arterial wall thickening and RELMα expression in the lung. CC10 IL-25 mice, but not CC10 IL-25 NKT^-/- mice, spontaneously developed pulmonary arterial wall thickening and RELMα expression in the lung at 6 months of age. Conclusions: Prolonged expression of IL-25 in the lung induces pulmonary arterial wall thickening by NKT cell-dependent mechanisms.

Allergic airway inflammation: key players beyond the Th2 cell pathway

“…Consistently, it has been shown that IL‐25 increases endothelial cell proliferation and formation of microvessel structures, suggesting that IL‐25 may also contribute to abnormal angiogenesis, one of features of airway remodeling in asthma. In this regard, we found that injection of neutralizing anti‐IL‐25 antibody inhibits antigen‐induced pulmonary arterial wall thickening and resistin‐like molecule‐α expression in chronic asthma models . Gregory et al .…”

“…have shown a positive correlation between mucosal IL‐33 expression and reticular basement membrane thickness in children with severe asthma. As discussed earlier, IL‐25 also participates in airway remodeling . Relative importance of these epithelial cytokines in steroid resistance and airway remodeling in asthma in humans remains an unsolved question.…”

The roles and functional mechanisms of interleukin-17 family cytokines in mucosal immunity

“…150,155 In addition to the induction of Th2 cytokines, one study showed that prolonged IL-17 expression in the lung induced NKT cell-dependent pulmonary arterial remodelling. 156 IL-17E also contributes to VEGF signaling-induced angiogenesis via the Erk/MAPK and PI3K/Akt pathways in asthma. 157 Moreover, blocking IL-17E in the airways of allergenFunctional mechanisms of IL-17 family cytokines X Song et al challenged mice decreases the deposition of peribronchial collagen and the hyperplasia of airway smooth muscles.…”

Mucosal-Resident T Lymphocytes with Invariant Antigen Receptors

“…There is ample evidence that in the lungs of mice iNKT cells carry out protective immune responses to infectious agents; some examples include the bacterium S. pneumoniae (Kinjo et al, 2011;Kawakami et al, 2003), fungi such as A. fumigatus (Albacker et al, 2013;Cohen et al, 2011), and influenza virus (De Santo et al, 2008;Ho et al, 2008). iNKT cells are also protective in diminishing lung fibrosis induced by bleomycin , but they are key participants in worsening pathogenesis in mouse models of chronic obstructive pulmonary disease Pichavant et al, 2013), models of acute lung injury (Shiga et al, 2014), ischemiareperfusion injury (Wallace et al, 2009), and lung remodeling induced in IL-25 transgenic mice (Kawashima et al, 2013).…”