Signaling via Tumor Necrosis Factor Receptor 1 but Not Toll-Like Receptor 2 Contributes Significantly to Hydrosalpinx Development following Chlamydia muridarum Infection

Abstract

Chlamydial infection in the lower genital tract can lead to hydrosalpinx, which is accompanied by activation of both pattern recognition receptor TLR2-and inflammatory cytokine receptor TNFR1-mediated signaling pathways. In the current study, we compared the relative contributions of these two receptors to chlamydial induction of hydrosalpinx in mice. We found that mice with or without deficiencies in TLR2 or TNFR1 displayed similar time courses of live organism shedding from vaginal swabs, suggesting that these receptor-mediated signaling pathways are not required for controlling chlamydial lower genital infection. However, mice deficient in TNFR1 but not TLR2 developed significantly reduced hydrosalpinx. The decreased pathogenicity correlated with a significant reduction in interleukin-17 by in vitro-restimulated splenocytes of TNFR1-deficient mice. Although TLR2-deficient mice developed hydrosalpinx as severe as that of wild-type mice, peritoneal macrophages from mice deficient in TLR2 but not TNFR1 produced significantly reduced cytokines upon chlamydial stimulation, suggesting that reduced macrophage responses to chlamydial infection do not always lead to a reduction in hydrosalpinx. Thus, we have demonstrated that the signaling pathways triggered by the cytokine receptor TNFR1 play a more significant role in chlamydial induction of hydrosalpinx than those mediated by the pattern recognition receptor TLR2, which has laid a foundation for further revealing the chlamydial pathogenic mechanisms.

Chlamydia muridarum Induction of Glandular Duct Dilation in Mice

“…Since Ͼ50% of the mice were induced to develop uterine horn dilation by C. muridarum infection and none of the uninfected mice developed any significant uterine dilation, we concluded that the uterine horn dilation was induced by C. muridarum infection. The hydrosalpinx from the same set of mice was also noted, and some of the results were previously published (8,15,26,28,41). Although mice with more severe uterine horn dilation seemed to lack hydrosalpinx in the oviduct in some cases, there was no significant correlation between uterine horn dilation and oviduct hydrosalpinx when all 88 mice were taken into consideration.…”

“…The following strains of wild-type and knockout (KO) mice used in the current study were all purchased from Jackson Laboratories (Bar Harbor, ME): C57BL/6J (JAX [Jackson Laboratories] stock number 000664), BALB/cJ (000651), C3H/HeJ (000659), TRIF KOs (005037), TIRAP KOs (017629), JNK2 KOs (004321), interleukin 1 receptor type I (IL-1R1) KOs (003245), IL-10 KOs (002251), and gamma interferon (IFN-␥) KOs (002287; 2 died before sacrifice). The pathology data for the remaining strains of mice used in the current study were acquired from the images and/or tissues of mice sacrificed in previous studies (8,15,24,26,28,41). The infection procedures were as follows.…”

“…Thus, it is necessary to characterize the C. muridarum-induced uterine horn dilation. Many previous mouse model-based studies grouped both hydrosalpinx and uterine horn dilation as upper genital tract pathology (19,20) and focused only on the fertility outcome (21)(22)(23) or patency of the upper genital tract (6) without differentiating uterine horn dilation from hydrosalpinx (8,(24)(25)(26)(27)(28). Although a previous study reported that interferon regulatory transcription factor 3 (IRF3) protected mice from uterine horn pathology during C. muridarum infection (13) and efforts have also been made to define host factors involved in C. muridarum induction of uterine horn dilation (29), the pathological basis of uterine horn dilation remains unclear.…”

Transcriptional Profiling of Human Epithelial Cells Infected with Plasmid-Bearing and Plasmid-Deficient Chlamydia trachomatis

“…The molecular basis for this attenuation is unclear but could involve plasmid-regulated genes (13) that function as Toll-like receptor 2 (14) or tumor necrosis factor alpha (TNF-␣) receptor antagonists (15,16). On the other hand, the basis of plasmid-mediated pathology might be a direct host-pathogen relationship caused by infection with virulent plasmid-bearing organisms.…”

Intrauterine Infection with Plasmid-Free Chlamydia muridarum Reveals a Critical Role of the Plasmid in Chlamydial Ascension and Establishes a Model for Evaluating Plasmid-Independent Pathogenicity

“…Thus, intravaginal inoculation of mice with C. muridarum has been used to study the mechanisms of C. trachomatis pathogenesis and immunity (3,(5)(6)(7). We recently optimized the C. muridarum mouse model by visually detecting long-lasting hydrosalpinges 8 weeks after infection (8)(9)(10)(11)(12). The C. muridarum murine model-based studies have led us to hypothesize that both adequate ascension to and induction of the appropriate inflammatory responses in the upper genital tract (UGT) are necessary for hydrosalpinx development.…”