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IL-4–secreting eosinophils promote endometrial stromal cell proliferation and prevent Chlamydia-induced upper genital tract damage

Significance Chlamydia trachomatis is the most common sexually transmitted bacterium, but most genital infections in women are asymptomatic. Consistent with this presentation, Chlamydia ascension into human endometrial tissue elicits robust innate and adaptive type 2 immunity. Herein, we genitally infected mice with C. trachomatis to explore the significance of type 2 innate immunity, finding that IL-4–secreting eosinophils promote endometrial stromal cell proliferation and prevent Chlamydia infection from triggering upper genital tract tissue destruction. Such results identify eosinophils as essential for repairing murine genital tissue repair after infectious insult. They also identify a need to define roles played by eosinophils in genital infections of women, and their role in other events associated with endometrial repair, including menstruation, endometritis, and endometriosis. Genital Chlamydia trachomatis infections in women typically are asymptomatic and do not cause permanent upper genital tract (UGT) damage. Consistent with this presentation, type 2 innate and TH2 adaptive immune responses associated with dampened inflammation and tissue repair are elicited in the UGT of Chlamydia-infected women. Primary C. trachomatis infection of mice also causes no genital pathology, but unlike women, does not generate Chlamydia-specific TH2 immunity. Herein, we explored the significance of type 2 innate immunity for restricting UGT tissue damage in Chlamydia-infected mice, and in initial studies intravaginally infected wild-type, IL-10−/−, IL-4−/−, and IL-4Rα−/− mice with low-dose C. trachomatis inoculums. Whereas Chlamydia was comparably cleared in all groups, IL-4−/− and IL-4Rα−/− mice displayed endometrial damage not seen in wild-type or IL-10−/− mice. Congruent with the aberrant tissue repair in mice with deficient IL-4 signaling, we found that IL-4Rα and STAT6 signaling mediated IL-4–induced endometrial stromal cell (ESC) proliferation ex vivo, and that genital administration of an IL-4–expressing adenoviral vector greatly increased in vivo ESC proliferation. Studies with IL-4-IRES-eGFP (4get) reporter mice showed eosinophils were the main IL-4–producing endometrial leukocyte (constitutively and during Chlamydia infection), whereas studies with eosinophil-deficient mice identified this innate immune cell as essential for endometrial repair during Chlamydia infection. Together, our studies reveal IL-4–producing eosinophils stimulate ESC proliferation and prevent Chlamydia-induced endometrial damage. Based on these results, it seems possible that the robust type 2 immunity elicited by Chlamydia infection of human genital tissue may analogously promote repair processes that reduce phenotypic disease expression.