Antigen-specific airway IL-33 production depends on FcγR-mediated incorporation of the antigen by alveolar macrophages in sensitized mice.

Although interleukin (IL)-33 is a candidate for the aggravation of asthma, the mechanisms underlying antigen-specific IL-33 production in the lung are unclear. Therefore, we analysed the mechanisms in mice. Intra-tracheal administration of ovalbumin (OVA) evoked increases in IL-33 and IL-33 mRNA in the lungs of both non-sensitized and OVA-sensitized mice, and the increases in the sensitized mice were significantly higher than in the non-sensitized mice. However, intra-tracheal administration of bovine serum albumin did not increase the IL-33 level in the OVA-sensitized mice. Depletion of neither mast cells/basophils nor CD4+ cells abolished the OVA-induced IL-33 production in sensitized mice, suggesting that the antigen recognition leading to the IL-33 production was not related with either antigen-specific IgE-bearing mast cells/basophils or memory CD4+ Th2 cells. When a fluorogenic substrate-labelled OVA (DQ-OVA) was intra-tracheally administered, the lung cells of sensitized mice incorporated more DQ-OVA than those of non-sensitized mice. The lung cells incorporating DQ-OVA included B-cells and alveolar macrophages. The allergic IL-33 production was significantly reduced by treatment with anti-FcγRII/III mAb. Depletion of alveolar macrophages by clodronate liposomes significantly suppressed the allergic IL-33 production, whereas depletion of B-cells by anti-CD20 mAb did not. These results suggest that the administered OVA in the lung bound antigen-specific IgG Ab, and then alveolar macrophages incorporated the immune complex through FcγRII/III on the cell surface, resulting in IL-33 production in sensitized mice. The mechanisms underlying the antigen-specific IL-33 production may aid in development of new pharmacotherapies.

Production of interleukin (IL)-33 in the lungs during multiple antigen challenge-induced airway inflammation in mice, and its modulation by a glucocorticoid.

Although interleukin (IL)-33 is a candidate aggravator of asthma, the cellular sources of IL-33 in the lungs during the progression of antigen-induced airway inflammation remain unclear. Furthermore, it has not been determined whether the antigen-induced production of IL-33 can be pharmacologically modulated in vivo. In this study, we examined the production of IL-33 in the lungs of sensitized mice during multiple intratracheal challenges with the antigen, ovalbumin. The 1st challenge clearly induced the IL-33 production in the lungs, and it was enhanced by the 2nd-4th challenges. IL-33 mRNA transcription was also induced after these challenges. An immunohistochemical analysis revealed that the cellular sources of IL-33 after the 1st challenge were mainly bronchial epithelial cells, while those after the 3rd challenge were not only the epithelial cells, but also inflammatory cells that infiltrated the lungs. Flow cytometric analyses indicated that approximately 20% and 10% of the IL-33-producing cells in the lungs were M2 macrophages and conventional dendritic cells, respectively. A systemic treatment with dexamethasone before the 1st challenge potently suppressed the IL-33 production. When dexamethasone was administered before the respective challenges, production of the IL-33 protein and the infiltration of IL-33-producing M2 macrophages and dendritic cells into the lungs in the 3rd challenge were also suppressed. In conclusion, the cellular sources of IL-33 in the lungs were dynamically altered during multiple challenges: not only bronchial epithelial cells, but also the M2 macrophages and dendritic cells that infiltrated the lungs produced IL-33. The production of IL-33 was susceptible to the glucocorticoid treatment.