Search

Background: Obesity-associated asthma is a phenotype of severe asthma. Late-onset, non-eosinophilic and female-dominant phenotype is highly symptomatic and difficult to treat. Leptin, an adipokine, exerts an immunomodulatory effect. IL-33 associated with innate immunity induces type 2 inflammation and is present in adipose tissue. The purpose of this study was to elucidate the pathogenesis of obesity-associated asthma by focusing on the interaction between leptin and IL-33., Methods: In leptin-deficient obese (ob/ob) and wild-type mice, IL-33 was instilled intranasally on three consecutive days. In part of the mice, leptin was injected intraperitoneally prior to IL-33 treatment. The mice were challenged with methacholine, and airway hyperresponsiveness (AHR) was assessed by resistance (Rrs) and elastance (Ers) of the respiratory system using the forced oscillation technique. Cell differentiation, IL-5, IL-13, eotaxin, keratinocyte-derived chemokine (KC) in bronchoalveolar lavage fluid (BALF) and histology of the lung were analyzed. For the in vitro study, NCI-H292 cells were stimulated with IL-33 in the presence or absence of leptin. Mucin-5AC (MUC5AC) levels were measured using an enzyme-linked immunosorbent assay., Results: Ob/ob mice showed greater Rrs and Ers than wild-type mice. IL-33 with leptin, but not IL-33 alone, enhanced Ers rather than Rrs challenged with methacholine in ob/ob mice, whereas it enhanced Rrs alone in wild-type mice. IL-33-induced eosinophil numbers, cytokine levels in BALF, eosinophilic infiltration around the bronchi, and goblet cell metaplasia were less in ob/ob mice than in wild-type mice. However, leptin pretreatment attenuated these changes in ob/ob mice. MUC5AC levels were increased by co-stimulation with IL-33 and leptin in vitro., Conclusions: Ob/ob mice show innate AHR. IL-33 with leptin, but not IL-33 alone, induces airway inflammation and goblet cell metaplasia and enhances AHR involving peripheral airway closure. This is presumably accelerated by mucus in ob/ob mice. These results may explain some aspects of the pathogenesis of obesity-associated asthma.

Allergic airway inflammation is one of the most typical characteristic features of bronchial asthma. T(h)2 cells, which produce IL-4, IL-5 and IL-13, are well known as major effector lymphocytes of the inflammation. In the present work, we found that subcutaneous injection of Toll-like receptor-9-ligand, CpG-oligodeoxynucleotides (CpG-ODN), remarkably suppressed eosinophilia and mucus hyper-production in T(h)2 cell-dependent airway inflammation model at the effector phase. The injection of CpG-ODN significantly blocked T(h)2 cell migration into lung. The inhibitory effects of CpG-ODN were observed even when IFN-gamma-deficient T(h)2 cells were transferred into IFN-gamma(-/-) mice. In contrast, the administration of neutralizing mAbs against type I cytokines such as IFN-alpha, IFN-beta and IL-12 significantly suppressed the inhibitory effect of CpG-ODN on airway inflammation and T(h)2 cell migration into the lung. We further demonstrated that the production of T(h)2 chemokines, thymus and activation-regulated chemokine (TARC) and macrophage-derived chemokine (MDC), was significantly reduced by the CpG-ODN. The reduction of both TARC and MDC was also inhibited by the blockade of IFN-alpha, IFN-beta and IL-12 with mAbs. Thus, we revealed here that IFN-alpha, IFN-beta and IL-12, but not IFN-gamma, were required for the inhibitory effect of CpG-ODN in T(h)2 cell-mediated allergic airway inflammation. The present evidence strongly suggest that induction of type I cytokines would be promising therapeutic targets in T(h)2-dependent allergic diseases such as bronchial asthma.

Adoptive cell transfer of an ovalbumin (OVA)-specific Th17-polarized cell population from transgenic DO11.10 mice into BALB/c mice followed by OVA inhalation caused airway hyperresponsiveness (AHR) with severe neutrophilia. The transferred Th17 cell population—previously polarized in vitro with IL-6, transforming growth factor-β and IL-23—contained negligible numbers of IFN-γ-producing cells; however, during Th17-cell-dependent airway inflammation, significant numbers of IFN-γ-producing cells—including cells producing both IL-17 and IFN-γ and cells producing only IFN-γ—were detected in the lung in addition to cells producing only IL-17. Using Th17-polarized cell populations derived from IL-17−/− or IFN-γ−/− mice, it was demonstrated that IL-17 is essential for inducing neutrophilic airway inflammation and that IFN-γ is required for the AHR elevation. IFN-γ appeared to be derived from cells producing both IL-17 and IFN-γ and/or from cells producing only IFN-γ, which were converted from the transferred Th17-polarized cell population. We also found that mAbs that neutralize IL-12 significantly suppressed the conversion of the Th17-polarized cell population toward IFN-γ producers in the lung; concomitantly, with this decreased conversion, IL-12 neutralization also attenuated the AHR elevation in the lung. IL-12-dependent conversion of the transferred Th17-polarized cell population into IFN-γ producers in the lung thus appeared to be a crucial process for inducing AHR elevation in Th17-cell-dependent airway inflammation. [ABSTRACT FROM PUBLISHER]

Mesenchymal stem cells (MSC) exert immune modulatory properties and previous studies demonstrated suppressive effects of MSC treatment in animal models of allergic airway inflammation. However, the underlying mechanisms have not been fully elucidated. We studied the role of MSC in immune activation and subsequent recruitment of monocytes in suppressing airway hyperresponsiveness and airway inflammation using a mouse model of allergic airway inflammation. MSC administration prior to or after allergen challenge inhibited the development of airway inflammation in allergen-sensitized mice. This was accompanied by an influx of CCR2-positive monocytes, which were localized around injected MSC in the lungs. Notably, IL-10-producing monocytes and/or macrophages were also increased in the lungs. Systemic administration of liposomal clodronate or a CCR2 antagonist significantly prevented the suppressive effects of MSC. Activation of MSC by IFN-γ leading to the upregulation of CCL2 expression was essential for the suppressive effects, as administration of wild-type MSC into IFN-γ-deficient recipients, or IFN-γ receptor-deficient or CCL2-deficient MSC into wild-type mice failed to suppress airway inflammation. These results suggest that MSC activation by IFN-γ, followed by increased expression of CCL2 and recruitment of monocytes to the lungs, is essential for suppression by MSC in allergen-induced airway hyperresponsiveness and airway inflammation. [ABSTRACT FROM AUTHOR]