In allergic asthma, inhalation of airborne allergens such as house dust mite (HDM) effectively activates both innate and adaptive immunity in the lung mucosa. To determine the role of the eicosanoid PGI2 and its receptor IP during allergic airway sensitization, HDM responses in mice lacking a functional IP receptor (IP−/−) were compared to wild type (WT) mice. Surprisingly, IP−/− mice had increased numbers of pulmonary CD3−NK1.1+Ly49b+ NK cells producing IFN-γ that was inversely associated with the number of type 2 innate lymphoid cells (ILC2s) expressing IL-33Rα and IL-13 compared to WT animals. This phenomenon was associated with elevated CX3CL1 levels in the airways of IP−/− mice and treatment with a neutralizing antibody to CX3CL1 reduced IFN-γ production by the lung NK cells. Remarkably, IP−/− mice were less responsive to HDM challenge than WT counterparts since intranasal instillation of the allergen induced markedly reduced levels of airway eosinophils, CD4+ lymphocyte infiltration and mucus production, as well as depressed levels of CCL2 chemokine and Th2 cytokines. NK cells were responsible for such attenuated responses since depletion of NK1.1+ cells in IP−/− mice restored both the HDM-induced lung inflammation and ILC2 numbers, while transfer of CD3−NK1.1+ NK cells into the airways of WT hosts suppressed the inflammatory response. Collectively, these data demonstrate a hitherto unknown role for PGI2 in regulating the number and properties of NK cells resident in lung tissue and reveal a role for NK cells in limiting lung tissue ILC2s and preventing allergic inflammatory responses to inhaled HDM allergen.
Allergic asthma is characterized by Th2 type inflammation, leading to airway hyperresponsivenes, mucus hypersecretion and tissue remodeling. S-Nitrosoglutathione reductase (GSNOR) is an alcohol dehydrogenase involved in the regulation of intracellular levels of S-nitrosothiols. GSNOR activity has been shown to be elevated in human asthmatic lungs, resulting in diminished S-nitrosothiols and thus contributing to increased airway hyperreactivity. Using a mouse model of allergic airway inflammation, we report that intranasal administration of a new selective inhibitor of GSNOR, SPL-334, caused a marked reduction in airway hyperreactivity, allergen-specific T cells and eosinophil accumulation, and mucus production in the lungs in response to allergen inhalation. Moreover, SPL-334 treatment resulted in a significant decrease in the production of the Th2 cytokines IL-5 and IL-13 and the level of the chemokine CCL11 (eotaxin-1) in the airways. Collectively, these observations reveal that GSNOR inhibitors are effective not only in reducing airway hyperresponsiveness but also in limiting lung inflammatory responses mediated by CD4+ Th2 cells. These findings suggest that the inhibition of GSNOR may provide a novel therapeutic approach for the treatment of allergic airway inflammation.
Our previous studies have shown that prostacyclin (PGI2) plays an important role in regulating mucosal inflammatory responses and the development of IL-17-producing innate T cells. Using mice lacking the PGI2 receptor, IP, we have investigated the role of this prostanoid in innate immune responses in the intestine. IL-22 belongs to the IL-10 family of cytokines and targets innate immune pathways due to the restricted expression of IL-22 receptors on innate cells critical to maintaining barrier function, such as epithelial cells. Our results revealed that IP receptor deficient mice (IP-/- mice) had a marked increase in intestinal IL-22 production by innate lymphoid cells, but a clear defect in IgA production. Importantly, the number of CD3-NKp46+ lymphoid cells was dramatically increased in the Peyer’s patch of IP-/- mice compared to wild-type animals and the cells produced high levels of IL-22 in response to IL-23 exposure. Concomitant with the enhanced IL-22 production, altered intestinal mucus production and reduced number of inter-follicular cells in the Peyer’s patch was observed in IP-/- mice compared to wild-type mice. Collectively, these results demonstrate that PGI2 plays a critical role in regulating IL-22 production and limiting NKp46+ lymphoid cell responses in the intestine. Since expression of IL-22 is induced in several human gut inflammatory conditions including Crohn’s disease, these findings may have implications in inflammatory bowel disease.
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