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

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.

A link between neutrophils and chronic disease manifestations of Chlamydia muridarum urogenital infection of mice.

Vigorous acute inflammatory responses accompany Chlamydia muridarum infections in mice and are positively correlated with adverse urogenital and respiratory tract infection outcomes in the mouse model. Thus, we tested the hypothesis that neutrophils induce an acute inflammatory insult that, in the repair phase, leads to the chronic sequelae of hydrosalpinx - a surrogate marker of infertility in the mouse model. To this end, we induced neutropenia in mice using a neutrophil-depleting monoclonal antibody during acute phases of C. muridarum urogenital infection only (days 2-21 postinfection). To prove induced neutropenia, peripheral blood was monitored for neutrophils during the treatment regimen. Neutropenic mice had a similar infection course as control mice, but had significantly reduced levels of certain histopathological parameters, reduced production of matrix metalloproteinase-9 (MMP-9) and reduced rates of hydrosalpinx following resolution of the infection. We conclude that neutrophils are a major source of MMP-9, a previously proved pathological factor in this model. Further, we conclude that acute inflammation in the form of neutrophils and neutrophil activation products are at least partially responsible for inducing the histological changes that ultimately result in fibrosis and infertility in the mouse model of chlamydial upper genital tract disease.