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

Genital infections in women typically are asymptomatic and do not cause permanent upper genital tract (UGT) damage. Consistent with this presentation, type 2 innate and T2 adaptive immune responses associated with dampened inflammation and tissue repair are elicited in the UGT of -infected women. Primary infection of mice also causes no genital pathology, but unlike women, does not generate -specific T2 immunity. Herein, we explored the significance of type 2 innate immunity for restricting UGT tissue damage in -infected mice, and in initial studies intravaginally infected wild-type, IL-10, IL-4, and IL-4Rα mice with low-dose inoculums. Whereas 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 infection), whereas studies with eosinophil-deficient mice identified this innate immune cell as essential for endometrial repair during infection. Together, our studies reveal IL-4-producing eosinophils stimulate ESC proliferation and prevent -induced endometrial damage. Based on these results, it seems possible that the robust type 2 immunity elicited by infection of human genital tissue may analogously promote repair processes that reduce phenotypic disease expression.