IL-25 and IL-33 Contribute to Development of Eosinophilic Airway Inflammation in Epicutaneously Antigen-Sensitized Mice

Abstract

BackgroundIL-25, IL-33 and TSLP are produced predominantly by epithelial cells and are known to induce Th2-type cytokines. Th2-type cytokines are involved not only in host defense against nematodes, but also in the development of Th2-type allergic diseases. TSLP was reported to be crucial for development of allergic airway inflammation in mice after inhalation of allergens to which they had been sensitized epicutaneously (EC) beforehand. However, the roles of IL-25 and IL-33 in the setting remain unclear.MethodsMice deficient in IL-25 and IL-33 were sensitized EC with ovalbumin (OVA) and then challenged intranasally with OVA. Airway inflammation, the number of inflammatory cells in bronchoalveolar lavage fluids (BALFs) and airway hyperresponsiveness (AHR) in the mice were determined, respectively, by histological analysis, with a hemocytometer, and by using plethysmograph chambers with a ventilator. Expression of mRNA in the skin and lungs was determined by quantitative PCR, while the BALF levels of myeloperoxidase (MPO) and eosinophil peroxidase (EPO) and the serum levels of IgE were determined by ELISA.Results Normal OVA-specific Th2- and Th17-cell responses of lymph nodes and spleens were observed in IL-25-deficient (IL-25-/-) and IL-33-/- mice after EC sensitization with OVA. Nevertheless, the number of eosinophils, but not neutrophils, in the BALFs, and the levels of Th2 cytokines, but not Th17 cytokines, in the lungs were significantly decreased in the IL-25-/- and IL-33-/- mice pre-sensitized EC with OVA, followed by inhalation of OVA, whereas their levels of AHR and OVA-specific serum IgE were normal.ConclusionsBoth IL-25 and IL-33 are critical for induction of Th2-type cytokine-mediated allergic airway eosinophilia, but not Th17-type cytokine-mediated airway neutrophilia, at the local sites of lungs in the challenge phase of mice sensitized EC with OVA. They do not affect OVA-specific T-cell induction in the sensitization phase.

Thymic stromal lymphopoietin and IL-33 promote skin inflammation and vaccinia virus replication in a mouse model of atopic dermatitis

“…In response to in vitro re-stimulation with OVA, splenocytes from Tslpr −/− and Il1rl1 −/− mice secreted comparable amounts of IL-4, IL-13, and IL-17A, as well as IFNγ as splenocytes from WT controls (Fig. 1E), consistent with previous observations in Tslpr −/− and Il33 −/− mice 56 . Thus, in contrast to other modes of immunization 7 , the systemic Th2 response to EC sensitization is not dependent on TSLP or IL-33.…”

Interleukin 17 Family Cytokines: Signaling Mechanisms, Biological Activities, and Therapeutic Implications

“…Consistent with the association of dysregulated Th2 responses with the development of allergy, IL-17E production is linked to the severity of chronic allergic conditions [44]. Thus, IL-17E-induced inflammation can be distinguished from IL-17A- and IL-17F-induced inflammation through the nature of the immune infiltrate, which mostly consists of eosinophils for the former and neutrophils for the latter [39]. However, IL-17E expression can be advantageous in some situations, as IL-17E can inhibit Th17 development through the induction of IL-13 by DCs and by inhibiting macrophage-derived IL-23 production [45].…”

“…At the protein level, IL-17E bears 16–20% sequence similarity to IL-17A, B and C. IL-17E derives from both hematopoietic and non-hematopoietic cells [38]. In mice, IL-17E is expressed by innate immune cells such as mast cells and alveolar macrophages in response to allergic stimuli [39]. This also seems to be true in humans, as blood eosinophils and basophils from normal and allergic subjects expressed IL-17E mRNA, which was further boosted upon IL-5 treatment [40].…”

IL-33 Promotes Food Anaphylaxis in Epicutaneously-Sensitized Mice By Targeting Mast Cells

“…Furthermore, IL-33 was shown not to be important for the homeostasis of skin MCs and intestinal MCs including MMC9s, or the expansion of small intestinal MCs following EC sensitization. In a recent report, IL-33 deficiency was found to protect EC-sensitized mice from anaphylaxis without a detectable effect on antigenspecific IgE antibody or Th2 responses 27 , 47 . TSLP and IL-25, which can promote Th2 responses, are released by tape stripped mouse skin (Ref.…”