IL-4-secreting eosinophils promote endometrial stromal cell proliferation and prevent <i>Chlamydia</i>-induced upper genital tract damage.

Abstract

Genital <i>Chlamydia trachomatis</i> infections in women typically are asymptomatic and do not cause permanent upper genital tract (UGT) damage. Consistent with this presentation, type 2 innate and T_H2 adaptive immune responses associated with dampened inflammation and tissue repair are elicited in the UGT of <i>Chlamydia</i>-infected women. Primary <i>C. trachomatis</i> infection of mice also causes no genital pathology, but unlike women, does not generate <i>Chlamydia</i>-specific T_H2 immunity. Herein, we explored the significance of type 2 innate immunity for restricting UGT tissue damage in <i>Chlamydia</i>-infected mice, and in initial studies intravaginally infected wild-type, IL-10^-/-, IL-4^-/-, and IL-4Rα^-/- mice with low-dose <i>C. trachomatis</i> inoculums. Whereas <i>Chlamydia</i> 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 <i>Chlamydia</i> infection), whereas studies with eosinophil-deficient mice identified this innate immune cell as essential for endometrial repair during <i>Chlamydia</i> infection. Together, our studies reveal IL-4-producing eosinophils stimulate ESC proliferation and prevent <i>Chlamydia</i>-induced endometrial damage. Based on these results, it seems possible that the robust type 2 immunity elicited by <i>Chlamydia</i> infection of human genital tissue may analogously promote repair processes that reduce phenotypic disease expression.