Distinct sustained structural and functional effects of interleukin‐33 and interleukin‐25 on the airways in a murine asthma surrogate

Abstract

SummaryInterleukin-25 (IL-25) and IL-33, which belong to distinct cytokine families, induce and promote T helper type 2 airway inflammation. Both cytokines probably play a role in asthma, but there is a lack of direct evidence to clarify distinctions between their functions and how they might contribute to distinct 'endotypes' of disease. To address this, we made a direct comparison of the effects of IL-25 and IL-33 on airway inflammation and physiology in our established murine asthma surrogate, which involves per-nasal, direct airway challenge. Intranasal challenge with IL-33 or IL-25 induced inflammatory cellular infiltration, collagen deposition, airway smooth muscle hypertrophy, angiogenesis and airway hyperresponsiveness, but neither increased systemic production of IgE or IgG1. Compared with that of IL-25, the IL-33-induced response was characterized by more sustained laying down of extracellular matrix protein, neoangiogenesis, T helper type 2 cytokine expression and elevation of tissue damping. Hence, both IL-25 and IL-33 may contribute significantly and independently to asthma 'endotypes' when considering molecular targets for the treatment of human disease.

The effects of interleukin‐33 on airways collagen deposition and matrix metalloproteinase expression in a murine surrogate of asthma

“…Previous studies have strongly implicated IL‐33 in playing a key role in the pathogenesis of the airways mucosal inflammation that typically accompanies human asthma . In our own previous studies we showed that direct, per‐nasal application of IL‐33 alone to the murine airway is sufficient to cause asthma‐like inflammation, including subepithelial deposition of collagens .…”

“…It is worth noting again, however, that IL‐33 challenge alone did not precisely recapitulate the effects of OVA sensitization and challenge because, for example, under the particular conditions of our experiments it did not result in elevation of MMP2 expression. Although we cannot discern the precise explanation for this, we speculate that one possible explanation is that, being a murine surrogate of ‘allergic asthma’, the airways inflammation induced in the OVA sensitization/challenge model is IgE‐dependent, whereas we previously detected no role for IgE in the airways inflammation induced by direct IL‐33 challenge . In this regard, it is interesting that deletion of the St2 gene partially but significantly reduced OVA‐induced MMP2 expression, suggesting that the IL‐33/ST2 axis does contribute, at least partially and indirectly, to the production of MMP2 in asthma.…”

“…FGFR4 signalling has been reported to synergize with that of TGF‐ β together to activate injury‐primed renal fibroblasts . Our previous data demonstrate that IL‐33 promotes the expression of TGF‐ β and bFGF . It is reasonable to postulate, therefore, that IL‐33 acts on the one hand to promote the synthesis of FGF and TGF‐ β , and on the other hand to increase the expression of FGFR4, both of which promote fibroblast collagen synthesis.…”

“…Immunoreactivity was measured using a Nikon microscope (Nikon, Tokyo, Japan) connected with a computer imaging system and analysed using proprietary software ( image‐pro plus 6.0; Media Cybernetics, Silver Spring, MD). The data were expressed as percentages of the positively stained areas in the entire lung sections as previously described …”

“…Specific inhibition of IL‐33 or its receptor ST2 has been reported to abrogate airways inflammation, mucus hypersecretion and airways hyper‐responsiveness in murine surrogates of asthma . Our own previous findings have shown that direct, per‐nasal application of IL‐33 alone to the respiratory tract can induce typical asthma‐like features in mice, including airways eosinophilic mucosal infiltration, hyperresponsiveness and neoangiogenesis . Recent studies indicate that IL‐33 is able to exert some of these effects indirectly by activating airways mucosal group 2 innate lymphoid cells (ILC2), inducing the latter to produce T helper type 2‐type cytokines .…”