Department of Comparative Medicine, Stanford University School of Medicine, Stanford, CA 94305;
Department of Comparative Medicine, Stanford University School of Medicine, Stanford, CA 94305.
Proc Natl Acad Sci U S A. 2017 Aug 15;114(33):E6892-E6901. doi: 10.1073/pnas.1621253114. Epub 2017 Aug 1.
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.
女性生殖道感染通常无症状，不会导致永久性上生殖道 (UGT) 损伤。与这种表现一致的是，与炎症抑制和组织修复相关的 2 型固有和 T2 适应性免疫反应在感染的女性 UGT 中被激发。小鼠的初次感染也不会引起生殖器病理学变化，但与女性不同的是，不会产生针对的 T2 免疫。在此，我们探讨了 2 型固有免疫对限制感染小鼠 UGT 组织损伤的意义，并在初步研究中用低剂量接种物经阴道感染野生型、IL-10、IL-4 和 IL-4Rα 小鼠。虽然在所有组中都能相当程度地清除，但 IL-4 和 IL-4Rα 小鼠表现出子宫内膜损伤，而在野生型或 IL-10 小鼠中未观察到。与缺乏 IL-4 信号传导的小鼠的异常组织修复一致，我们发现 IL-4Rα 和 STAT6 信号介导了 IL-4 诱导的子宫内膜基质细胞 (ESC) 增殖，并且生殖器给予表达 IL-4 的腺病毒载体大大增加了体内 ESC 增殖。用 IL-4-IRES-eGFP（4get）报告小鼠进行的研究表明，嗜酸性粒细胞是主要的产生 IL-4 的子宫内膜白细胞（在固有和感染期间），而用嗜酸性粒细胞缺陷小鼠进行的研究表明，这种固有免疫细胞对于感染期间的子宫内膜修复是必需的。总的来说，我们的研究表明，产生 IL-4 的嗜酸性粒细胞刺激 ESC 增殖并防止感染引起的子宫内膜损伤。基于这些结果，似乎有可能感染人类生殖器组织引起的强烈 2 型免疫可能类似地促进减少表型疾病表达的修复过程。
