Xiujuan Yao

Direct comparison of the dynamics of IL‐25‐ and ‘allergen’‐induced airways inflammation, remodelling and hypersensitivity in a murine asthma model

Interleukin‐25 has been implicated in the pathogenesis of asthma from studies on human asthmatics and in murine asthma models.

Interleukin-25 promotes basic fibroblast growth factor expression by human endothelial cells through interaction with IL-17RB, but not IL-17RA.

Unlike other IL‐17 family members, the Th2‐derived cytokine IL‐25 (IL‐17E) induces (promotes) Th2 responses. One or both of the two receptors for IL‐25 (IL‐17RA, IL‐17RB) is expressed on inflammatory cells and tissue structural cells, suggesting that in addition to promoting Th2‐type inflammation IL‐25 may also act on structural cells at sites of Th2‐type inflammation such as in the asthmatic bronchial mucosa to promote remodelling changes.

Interleukin (IL)-25: Pleiotropic roles in asthma.

IL‐25, also named IL‐17E, is a distinct member of the IL‐17 cytokine family, which can promote and augment T helper type 2 (Th2) responses locally or systemically. Growing evidence from experimental and clinical studies indicates that the expression of IL‐25 and its cognate receptor, IL‐17RB/RA, is markedly upregulated in asthmatic conditions. It has also been found that IL‐25 induces not only typical eosinophilic inflammation and airway hyperresponsiveness (AHR), but also airway remodelling, manifested by goblet cell hyperplasia, subepithelial collagen deposition and angiogenesis. This review will focus on the discovery, cellular origins and targets of IL‐25, and try to update current animal and human studies elucidating the roles of IL‐25 in asthma. We conclude that although IL‐25 is a pleiotropic cytokine, it may only play its dominant role in a certain specific asthmatic endotype, named ‘IL‐25 high’ phenotype. Thus, targeting IL‐25 or its receptor might selectively benefit some subgroups with asthma. Furthermore, the major IL‐25 producing as well as responsive cells in the changeable milieu of asthma should be assessed in the future.

Characteristics of IL-25 and allergen-induced airway fibrosis in a murine model of asthma.

Interleukin (IL)‐25 has been implicated in the pathogenesis of human asthma by inducing a Th2 cytokine response, but its possible role in the development of airway remodelling is less clear.

Comprehensive attenuation of IL-25-induced airway hyperresponsiveness, inflammation and remodelling by the PI3K inhibitor LY294002

Existing in vitro and in vivo studies suggest that both IL‐25 and phosphoinositide 3‐kinases (PI3Ks) exhibit broad effects on the functions of immune cells implicated in the pathogenesis of asthma. Whether the blockade of PI3K signalling directly inhibits the asthma relevant pathogenetic changes induced by IL‐25 in an in vivo condition is still unclear. Using an established IL‐25‐induced murine model of asthma, we undertook a comprehensive evaluation of the effects of co‐administered LY294002, a pharmacological pan‐inhibitor of PI3K on IL‐25‐induced changes on this model, with particular regard to airway remodelling.

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

Interleukin‐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 hyper‐responsiveness, 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.

Age-related activation of MKK/p38/NF-κB signaling pathway in lung: from mouse to human.

We and others previously reported that the pro-inflammatory cytokine tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and IL-6 significantly accumulate with age in mouse lung. This is accompanied by elevated phosphorylation of p38. Here, we further investigate whether aging affects activation of p38 signaling and the inflammatory reaction after exposure to lipopolysaccharide (LPS) in the lungs of mice in vivo and humans ex vivo. The data showed that activation of p38 peaked at 0.5h and then rapidly declined in young (2-month-old) mouse lung, after intranasal inhalation challenge with LPS. In contract, activation of p38 peaked at 24h and was sustained longer in aged (20-month-old) mice. As well as altered p38, activations of its upstream activator MKK and downstream substrate NF-κB were also changed in the lungs of aged mice, which corresponded with the absence in the early phase but delayed increases in concentrations of TNF-α, IL-1β and IL-6. Consistent with the above observations in mice, similar patterns of p38 signaling also occurred in human lungs. Compared with younger lungs from adult-middle aged subjects, the activation of p38, MKK and NF-κB, as well as the production of pro-inflammatory cytokines were significantly increased in the lungs of older subjects ex vivo. Exposure of human lung cells to LPS induced rapid activation of p38, MKK and NF-κB in these cells from adult-middle aged subjects, but not older subjects, with increases in the production of the pro-inflammatory cytokines. The LPS-induced rapid activation in the lung cells from adult-middle aged subjects occurred as early as 0.25h after exposure, and then declined. Compared with adult-middle aged subjects, the LPS exposure did not induce marked changes in the early phase, either in the activation of p38, MKK and NF-κB, or in the production of TNF-α, IL-1β or IL-6 in the lung cells from older subjects. In contrast, these changes occurred relatively late, peaked at 16h and were sustained longer in the lungs of older subjects. These data support the hypothesis that the sustained activation of the p38 signaling pathway at baseline and the absence in the early phase but delayed of p38 signaling pathway response to LPS in the elderly may play important roles in increased susceptibility of aged lungs to inflammatory injury.

Altered Th1/Th2 commitment contributes to lung senescence in CXCR3-deficient mice.

Aging is an inevitable process associated with immune imbalance, which is characterized by a progressive functional decline in major organs, including lung. However, effects of altered Th1/Th2 commitment on lung senescence are largely unknown. To examine effects of altered Th1/Th2 balance on lung aging, we measured proportions of Th1 and Th2 cells and expression of cytokines, chemokines, collagen deposition and other relevant physiological and pathological parameters in 2- and 20-months-old (mo) CXCR3-deficient (CXCR3(-/-)) C57BL/6J mice compared with wild-type (WT) mice. There was a significant weight-loss observed in 20-mo CXCR3(-/-) mice compared with the same aged WT group. Although lung function and structure changed with age in both groups, central airway resistance (Rn), tissue elastance (H) and damping (G) were significantly lower in 20-mo CXCR3(-/-) mice than those of WT mice. In contrast, the whole lung volume (V(L)), the mean linear intercept length of alveolar (L(m)), and the total lung collagen content were significantly elevated in 20-mo CXCR3(-/-) mice. With aging, the lungs of WT mice had typical Th1-type status (increased population of Th1 cells and concentrations of cytokine IFN-γ and CXCR3 ligands) while CXCR3(-/-) mice showed Th2-type polarization (decreased proportion of Th1 cells and concentrations of CXCR3 ligands but increased level of IL-4). Our data suggest that Immunosenescence is associated with lung aging, and that altered Th1/Th2 imbalance favors Th2 predominance in CXCR3(-/-) mice, which contributes to the process of accelerated lung aging in this model.