Background/Purpose: The sterile inflammatory arthritis associated with spondylitis, uveitis and rash, known as reactive arthritis, commences a few weeks after certain gastrointestinal or genitourinary infections, including Salmonella and Chlamydia in genetically-susceptible patients. ZAP-70^W163C mutant BALB/c mice (known as SKG) develop a syndrome highly similar to human reactive arthritis after vaginal infection with C. muridarum. In that model, Chlamydial DNA was found in splenic and lymph node CD11b+ cells distant from the site of infection. We hypothesized that monocytes and macrophages disseminate pro-inflammatory C. muridarum pathogen-associated inflammatory molecules (PAMPs) to distant sites in susceptible SKG mice to induce inflammatory cytokine-mediated pathology.

Methods: Female SKG and BALB/c mice were genitally infected with C. muridarum. Arthritis was assessed weekly for 12 weeks post-infection. Joint sections were scored after sacrifice and genital tracts were analyzed 1 week post-infection. We compared Hspa5, Tgtp1, IL-23 expression by RT-qPCR in genital tract from SKG mice before or 1 week after infection. Anti-TNF or isotype were delivered either immediately after infection or after arthritis developed. We engineered C. muridarum expressing luciferase and GFP (pGFP-Luc-CM) to monitor in vivo uptake and dissemination. We depleted macrophages from Chlamydia-infected SKG mice with clodronate liposomes.

Results: SKG but not BALB/c mice developed typical histological features of chronic reactive arthritis but remained autoantibody-negative, from 5 weeks after genital infection. When applied at infection, anti-TNF blocked C. muridarum-induced reactive arthritis in SKG mice. Seven weeks post-infection, SKG but not BALB/c mice developed inflammatory salpingitis. One week post-infection, we observed C. muridarum dissemination in the upper genital tract of SKG but not BALB/c mice. After infection with pGFP-Luc-CM, C. muridarum GFP signal was exclusively found in CD11b+Ly6g-Lyc6c+F4/80+MHC class II+ macrophages in both strains. Expression of macrophage Tgtp1 and IL23a but not Hspa5 expression was upregulated one week after C. muridarum infection and returned to baseline levels 5 weeks after infection. Tgtp1 and IL23a mRNA expression were highly correlated (Figure) in genital tract one week upon infection. Depletion of macrophages using clodronate liposomes just prior to infection prevented arthritis.

Conclusion: These data indicate that macrophages, IL-23 and TNF are required for the development of Chlamydia-induced reactive arthritis in SKG mice. Macrophages exclusively take up Chlamydia from the site of infection and, in susceptible mice/individuals, upregulate autophagy and IL-23 production and transport persistent bacteria to distant sites such as upper genital tract and joints to trigger TNF-mediated inflammatory pathology.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/chlamydia-infected-macrophages-trojan-horses-for-dissemination-of-il-23-and-tnf-mediated-inflammation-in-skg-mouse-reactive-arthritis/