Abstract
Sex differences in asthma prevalence are well-documented but poorly understood. Murine models have contributed to our understanding of mechanisms that could regulate this sex disparity, though the majority of these studies have examined responses present after Th2 adaptive immunity is established. We have now investigated how sex influences acute activation of innate cell populations in the lung upon initial exposure to the model antigen, ovalbumin (OVA), in the presence of IL-33 (OVA+IL-33), to prime the lungs for type 2 immunity. We also examined how inflammatory responses induced by OVA+IL-33 were altered in mice lacking the STAT6 transcription factor, which is activated by IL-13, an effector cytokine of IL-33. Our data demonstrate that type 2 inflammation induced by OVA+IL-33 was more severe in female mice compared to males. Females exhibited greater cytokine and chemokine production, eosinophil influx and activation, macrophage polarization to the alternatively activated phenotype, and expansion of group 2 innate lymphoid cells (ILC2s). While increases in ILC2s and eosinophils were largely independent of STAT6 in both males and females, many other responses were STAT6-dependent only in female mice. Our findings indicate that a subset of type 2 inflammatory responses induced by OVA+IL-33 require STAT6 in both males and females and that enhanced type 2 inflammation in females, compared to males, is associated with greater IL-13 protein production. Our findings suggest blunted IL-13 production in males may protect against type 2 inflammation initiated by OVA+IL-33 delivery to the lung.
Highlights
Allergic asthma is a type 2-biased chronic inflammatory disease of the airways, historically considered to be orchestrated by CD4+ Th2 cells driving maladaptive responses in innate immune cells and structural cells of the lung [1]
In mice treated with OVA alone, there were no significant differences between males and females or between wild type (WT) and STAT6-KO mice: very few eosinophils were present and the majority of bronchoalveolar lavage fluid (BALF) cells were macrophages (Figures 1A,B and data not shown)
In mice treated with OVA+IL-33, WT females had significantly more total BALF cells (Figure 1B) and eosinophils (Figure 1C) compared to WT males
Summary
Allergic asthma is a type 2-biased chronic inflammatory disease of the airways, historically considered to be orchestrated by CD4+ Th2 cells driving maladaptive responses in innate immune cells and structural cells of the lung [1]. Recent interest has expanded to better understand mechanisms by which innate cells promote allergic airways disease, with particular attention on group 2 innate lymphoid cells (ILC2s) and the cytokines that activate them: IL-33, TSLP, and IL-25 [2] Both the incidence and severity of asthma and allergies have been increasing steadily over the last two to three decades, with at least 300 million asthma sufferers worldwide and asthma ranking as one of the costliest of all chronic diseases [3]. Consistent with the pro-inflammatory role of estrogens, eosinophilic inflammation in these models is reduced both by ovariectomy and treatment with tamoxifen, an estrogen antagonist [10] Most of these studies have relied upon systemic sensitization of mice with ovalbumin (OVA) in the presence of alum as a Th2-skewing adjuvant. Evidence that ILC2s do not participate in allergic airways disease in systemically sensitized mice [11] suggests that the contribution of androgens and ILC2s in sex-specific responses in murine models of asthma may have been overlooked
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