IL-33-Responsive Group 2 Innate Lymphoid Cells Are Regulated by Female Sex Hormones in the Uterus [INNATE IMMUNITY AND INFLAMMATION]

Abstract

Group 2 innate lymphoid cells (ILC2s) reside in multiple organs in the body, where they play roles in immunity, tissue homeostasis, and metabolic regulation. However, little is known about the regulatory mechanisms of ILC2s in different organs. Here, we identified ILC2s in the mouse uterus and found that they express cell surface molecules, including the IL-33 receptor, ST2, that are roughly comparable to those expressed by lung ILC2s. Both in vivo and in vitro treatment with IL-33 induced type 2 cytokine production in uterine ILC2s, suggesting that they respond to IL-33 in a manner similar to ILC2s in other organs. Importantly, uterine ILC2s were nearly absent in ovariectomized mice and were increased in wild-type mice by estrogen administration, whereas lung ILC2s were unaffected by both ovariectomy and estrogen administration. Likewise, a marked reduction in uterine ILC2s was observed in mice deficient in estrogen receptor α or estrogen receptor β. Furthermore, uterine ILC2s highly expressed estrogen receptor α, and in vitro culture of isolated uterine ILC2s with 17β-estradiol modified expression of a number of genes. Finally, an increased prevalence in neonatal mortality was observed in litters from dams lacking the IL-33 receptor, ST2. Taken together, our findings indicate that unlike lung IL2Cs, uterine ILC2s are regulated by female sex hormones, which may specialize them for specific physiological functions.

Footnotes

  • This work was supported by grants from the National Institutes of Health, Grants R01 AI71106 and R01 HL117823, and the Mayo Foundation.

  • The microarray data presented in this article have been submitted to the ArrayExpress database (https://www.ebi.ac.uk/arrayexpress) under accession number E-MTAB-5789.

  • The online version of this article contains supplemental material.

  • Abbreviations used in this article:

    E2
    17β-estradiol
    ERα
    estrogen receptor α
    ERβ
    estrogen receptor β
    FRT
    female reproductive tract
    ILC
    innate lymphoid cell
    ILC2
    group 2 ILC
    Lin
    lineage-negative
    OVX
    ovariectomized
    P4
    progesterone
    qRT-PCR
    quantitative RT-PCR
    WT
    wild-type.
  • Received December 9, 2016.
  • Accepted October 14, 2017.

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