Asthma prevalence is greater in boys than girls, but around puberty there is a shift in asthma prevalence, and at mid-life women are about two times more likely than men to have asthma. This suggests a role for sex hormones in asthma pathogenesis; however the mechanisms remain unknown. Group 2 innate lymphoid cells (ILC2) are important in driving the initial phase of allergic airway inflammation that is associated with asthma. ILC2 are activated by IL-33, TSLP, and IL-25 which are upregulated in response to airway allergens, including Alternaria alternata. Upon stimulation, ILC2 have increased expression of the transcription factors GATA3 and ROR? and produce IL-5 and IL-13. IL-5 and IL-13 increase the infiltration of eosinophils, airway hyperresponsiveness (AHR), and mucus production, all hallmarks of asthma. Our preliminary data showed IL- 33-stimulated ILC2 from female mice had significantly increased IL-5 and IL-13 protein expression compared to ILC2 from male mice. Therefore, we hypothesize that the ovarian hormones, 17beta-estradiol (17?-E2) and progesterone (P4), increase ILC2-induced airway inflammation.
In Aim 1 we will determine the mechanisms by which sex hormones increase IL-5 and IL-13 production from ILC2. Sham-operated female and male mice, ovariectomized female mice, and orchidectomized male mice will be administered pellets containing vehicle, 17?-E2, P4, and/or testosterone. ILCs will be harvested from the bone marrow and lungs of these mice and stimulated with IL-33 ex vivo. IL-5 and IL-13 protein expression, ROR? and GATA3 mRNA expression, and surface expression of ST2, a component of the IL-33 receptor, will then be determined in ILC2.
In Aim 2, we will determine the role of ovarian hormones on Alternaria extract (Alt Ex)-induced innate immune-mediated airway inflammation. WT BALB/c female, male, ovariectomized, and orchidectomized mice will be challenged with Alt Ex for 4 days to initiate an innate immune response. We will then determine ILC2 cytokine expression, airway inflammation, AHR, and mucus production. This proposal will delineate a mechanism(s) by which sex hormones regulate ILC2, and it may identify potential therapeutic targets for patients, in particular women, with asthma.
We will determine how the sex hormones affect protein secretion from group 2 innate immune lymphoid cells that are associated with increased airway inflammation, airway hyperresponsiveness, and mucus production seen in asthma. Our findings will determine if sex hormones differentially regulate ILC2 cytokine expression and may determine potential therapeutic targets to for patients, in particular women, with asthma.
|Fuseini, Hubaida; Yung, Jeffrey A; Cephus, Jacqueline Yvonne et al. (2018) Testosterone Decreases House Dust Mite-Induced Type 2 and IL-17A-Mediated Airway Inflammation. J Immunol 201:1843-1854|
|Yung, Jeffrey A; Fuseini, Hubaida; Newcomb, Dawn C (2018) Hormones, sex, and asthma. Ann Allergy Asthma Immunol 120:488-494|
|Celada, Lindsay J; Kropski, Jonathan A; Herazo-Maya, Jose D et al. (2018) PD-1 up-regulation on CD4+ T cells promotes pulmonary fibrosis through STAT3-mediated IL-17A and TGF-?1 production. Sci Transl Med 10:|
|Stier, Matthew T; Goleniewska, Kasia; Cephus, Jacqueline Y et al. (2017) STAT1 Represses Cytokine-Producing Group 2 and Group 3 Innate Lymphoid Cells during Viral Infection. J Immunol 199:510-519|
|Fuseini, Hubaida; Newcomb, Dawn C (2017) Mechanisms Driving Gender Differences in Asthma. Curr Allergy Asthma Rep 17:19|
|Cephus, Jacqueline-Yvonne; Stier, Matthew T; Fuseini, Hubaida et al. (2017) Testosterone Attenuates Group 2 Innate Lymphoid Cell-Mediated Airway Inflammation. Cell Rep 21:2487-2499|
|Zhou, Weisong; Zhang, Jian; Goleniewska, Kasia et al. (2016) Prostaglandin I2 Suppresses Proinflammatory Chemokine Expression, CD4 T Cell Activation, and STAT6-Independent Allergic Lung Inflammation. J Immunol 197:1577-86|
|Bloodworth, Melissa H; Newcomb, Dawn C; Dulek, Daniel E et al. (2016) STAT6 Signaling Attenuates Interleukin-17-Producing ?? T Cells during Acute Klebsiella pneumoniae Infection. Infect Immun 84:1548-1555|
|Zhou, Weisong; Toki, Shinji; Zhang, Jian et al. (2016) Prostaglandin I2 Signaling and Inhibition of Group 2 Innate Lymphoid Cell Responses. Am J Respir Crit Care Med 193:31-42|
|Banathy, Alex; Cheung-Flynn, Joyce; Goleniewska, Kasia et al. (2016) Heat Shock-Related Protein 20 Peptide Decreases Human Airway Constriction Downstream of ?2-Adrenergic Receptor. Am J Respir Cell Mol Biol 55:225-33|
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