A role for CXC chemokine receptor-2 in the pathogenesis of urogenital Chlamydia muridarum infection in mice

Abstract

We tested the hypothesis that a specific chemokine receptor, CXC chemokine receptor-2 (CXCR2), mediates acute inflammatory damage during chlamydial urogenital infection, which ultimately leads to the chronic sequelae of hydrosalpinx - a surrogate marker of infertility. Homozygous CXCR2 genetic knockouts (CXCR2-/-), heterozygous littermates (CXCR2+/-) or homozygous wild-type (wt) controls (CXCR2+/+) were infected intravaginally with Chlamydia muridarum. Although no change was observed in the infection in the lower genital tract based on CXCR zygosity, a delay in the ascension of infection into the upper genital tract was seen in CXCR2-/- mice. Significantly elevated peripheral blood neutrophil counts were observed in CXCR2-/- mice when compared with controls. Reduced rates of acute inflammatory indices were observed in the affected tissue, indicating reduced neutrophil extravasation capacity in the absence of CXCR2. Of note was a reduction in the postinfection development of hydrosalpinx that correlated with CXCR2 zygosity, with both CXCR2-/- (13%) and their CXCR2+/- (35%) littermates displaying significantly lower rates of hydrosalpinx formation than the wt CXCR2-sufficient mice (93%). We conclude that CXCR2 ligands are a major chemotactic signal that induces damaging acute inflammation and the resulting chronic pathology during the repair phase of the host response, but are dispensable for the resolution of infection.

Enhanced Neutrophil Longevity and Recruitment Contribute to the Severity of Oviduct Pathology during Chlamydia muridarum Infection

“…These data correspond with our findings that CM3.1 exhibits a reduced ability to induce cytokine production by cervical epithelial cells (31). In addition, a previous study revealed that mice deficient in CXCR2, the receptor for CXCL1 and CXCL2, exhibit significant reductions in acute inflammation in the oviducts during C. muridarum infection, indicating that these chemokines play a role in migration of neutrophils to the genital tract (24).…”

“…Studies with the mouse model have supported this correlation by revealing that enhanced and/or prolonged neutrophil influx into the oviducts is associated with the development of hydrosalpinx (8,42). In addition, mice deficient in the chemokine receptor CXCR2 display reduced acute inflammation and lower rates of hydrosalpinx, and strains of mice with elevated CXCL2 production exhibit worse disease (9,24). Neutrophils likely contribute to pathology by releasing mediators that directly damage reproductive tract tissues, and neutrophil release of the proteolytic enzyme matrix metalloproteinase 9 (MMP9) has been implicated in the development of scarring and fibrosis of the murine oviduct after chlamydial infection (16,38).…”

Complement Factor C5 but Not C3 Contributes Significantly to Hydrosalpinx Development in Mice Infected with Chlamydia muridarum

“…The same study also revealed that tumor necrosis factor receptor 1 (TNFR1) was critical for hydrosalpinx development following C. muridarum infection, which is consistent with an earlier observation showing an important role of tumor necrosis factor alpha (TNF-␣) in chlamydial induction of hydrosalpinx (14). Many other host molecules have also been shown to contribute to chlamydial pathogenicity in the upper genital tract, including matrix metalloproteinases (15), inducible nitric oxide synthase (16), interleukin 1 (IL-1) receptor (17), caspase 1 (18,19), IL-17 (20), CD28 (21), and CXCR2 (22). However, none of these previous studies have sufficiently addressed whether the reduced pathology was due to reduced oviduct infection, reduced inflammatory responses in the oviduct, or both.…”

Identification of Antigen-Specific Antibody Responses Associated with Upper Genital Tract Pathology in Mice Infected with Chlamydia muridarum

“…A mouse model with intravaginal infection with Chlamydia muridarum, also known as the mouse biovar of C. trachomatis, has been extensively used to study C. trachomatis pathogenesis and immunology (12,13,17,31,32,38,41,43). This is because C. muridarum-infected mice can develop upper genital tract pathologies similar to those occurring in women after they acquire C. trachomatis infection (43,48).…”