PGI2 Controls Pulmonary NK Cells That Prevent Airway Sensitization to House Dust Mite Allergen

Abstract

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.

Type two innate lymphoid cells: the Janus cells in health and disease

“…In a mouse model of Alternaria alternata‐driven severe asthma, PGI2‐receptor deficiency augmented whereas administration of PGI2 analog suppressed IL‐5 and IL‐13 production by lung ILC2s, airway eosinophilia and mucus production score in the airways . The findings of this study, however, were conflicted by a more recent study in which they showed that in the absence of PGI2‐receptor, IFN‐γ producing pulmonary NK cells were expanded, house dust mite‐induced airway eosinophilia and airway mucus production were reduced . It remains to be addressed whether the seeming discrepancy between the two studies are caused by the type of allergen and allergen exposure protocol.…”

“…69 The findings of this study, however, were conflicted by a more recent study in which they showed that in the absence of PGI2-receptor, IFNγ producing pulmonary NK cells were expanded, house dust mite-induced airway eosinophilia and airway mucus production were reduced. 70 It remains to be addressed whether the seeming discrepancy between the two studies are caused by the type of allergen and allergen exposure protocol.…”

The group 2 innate lymphoid cell (ILC2) regulatory network and its underlying mechanisms

“…However, another study provided different observation that IP‐deficient mice exhibit increased numbers of IFN‐γ − producing NK cells. Considering that IFN‐γ is a negative regulator for ILC2s, NK cell depletion results in a rise in the number of ILC2s in IP‐deficient mice . Thus, PGI2 might directly suppress ILC2s, but also indirectly regulate ILC2s via NK cells.…”

Role of NKp46 + natural killer cells in house dust mite‐driven asthma

“…Cardinal features of HDM-induced allergic asthma are not influenced by NKp46 + cell absence during the sensitization or challenge phase only In NKp46-DTA mice, ablation of NKp46 + NK cells occurs early during their maturation in the bone marrow (Narni-Mancinelli et al, 2011), raising the possibility of functional replacement of NK cells by other immune cell types during immune development. Moreover, previous studies have suggested that NK cells can fulfill opposing roles during asthma, depending on the models used (Korsgren et al, 1999;Ple et al, 2010;Ghadially et al, 2013;Farhadi et al, 2014;Ferrini et al, 2016;Simons et al, 2017;Wan Jiacheng Bi et al, 2017). We therefore considered the possibility that NK cells might have contrasting roles in the sensitization and challenge phase of the HDM-induced asthma model, which might be obscured in animals constitutively lacking NK cells.…”

“…These studies showed that NK cells were crucial and non-redundant for asthma development induced by ovalbumin (OVA)/alum (Korsgren et al, 1999;Ple et al, 2010;Ghadially et al, 2013) or chronic HDM exposure (Farhadi et al, 2014). In contrast, increased pulmonary NK cell numbers were recently correlated with reduced HDM-mediated airway inflammation in mice (Ferrini et al, 2016;Simons et al, 2017). Moreover, antibody-mediated NK cell depletion was shown to increase eosinophilia and goblet cell hyperplasia in early papain-or bleomycin-induced lung inflammation (Wan Jiacheng Bi et al, 2017).…”