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

Abstract

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.

The emerging roles of eosinophils in mucosal homeostasis

“…67,68 However, despite this observation, eosinophil-deficient mice exhibit normal pregnancy and parturition, suggesting that the role of eosinophils in this process is redundant, or that adaptation takes place to compensate for its absence. 13 Nonetheless, a recent study by Vicetti Miguel et al, 17 suggests that eosinophils play a critical role in endometrial maintenance during infection with Chlamydia trachomatis. Genital C. trachomatis infection promoted type II immune responses, with IL-4 signaling required for clearing infection and preventing endometrial damage.…”

“…Genital C. trachomatis infection promoted type II immune responses, with IL-4 signaling required for clearing infection and preventing endometrial damage. 17 The use of IL-4-IRES-eGPF (4get) mice revealed eosinophils as the main source of IL-4 present during, suggesting a central role for these cells in promoting endometrial repair. 17 Lung development and immunity Eosinophils are not present in the lung of mice at birth but increase (together with ILC2s, basophils and mast cells) to reach maximal levels between postnatal day 7 and 14.…”

“…10,16 In the uterus, there is an estimated 1 × 10 5 cells within the uterine horn but this number varies depending on the estrus cycle, with the highest eosinophil recruitment at peak. 13,17 Similarly, eosinophil numbers in the thymus and mammary gland also fluctuate over time. While eosinophils are recruited to the cortico-medullary region (CMR) of the thymus during fetal development, peaking around 2 weeks after birth, their numbers decrease shortly thereafter and only rise again, in both the CMR and medullary region, around 16 weeks corresponding to the time of thymic involution.…”

TGFβ1 mimetic peptide modulates immune response to grass pollen allergens in mice

“…In order to investigate the modulatory capacity of the TGFβ1-mim on Th2 polarization in vivo, we used the 4get mouse model, which possesses a bicistronic mRNA linking a readily identifiable reporter (eGFP) to the IL-4 gene expression. 26,27,61,62 In this model, recombinant Phl p 5 alone was not able to induce expression of eGFP in CD4 + T cells. In a recent study, we could show that birch pollen extracts promoted Th2 polarization in the 4get mouse model whereas purified recombinant Bet v 1 did not.…”

CCR3 antagonist impairs estradiol induced eosinophil migration to the uterus in ovariectomized mice

“…In the stages of proestrus and estrus the amount of circulating estrogen is enhance, and the rodents are susceptible to mating, thus the uterus presents a higher proportion of the granulocyte (9), possibly to ensure an effective response in the recognition of paternal antigens and / or defense against pathogens that can be transferred at the moment of mating (Mamata De, 1991). Accordingly, eosinophils performed this protective function by releasing (IL)-4 into the uterus after Chlamydia infection in mice (10).…”