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Updated: Nov 21, 2025
An Adoptive Transfer Model of Rheumatoid Arthritis in Mice
Published on: June 6, 2025
Mediation of Interleukin-23 and Tumor Necrosis Factor-Driven Reactive Arthritis by Chlamydia-Infected Macrophages in
Xavier Romand1, Xiao Liu2, M Arifur Rahman2
1Université Grenoble Alpes, GREPI TIMC-IMAG, UMR 5525, Grenoble, France.
Objective:
ZAP-70W163C BALB/c (SKG) mice develop reactive arthritis (ReA) following infection with Chlamydia muridarum. Since intracellular pathogens enhance their replicative fitness in stressed host cells, we examined how myeloid cells infected with C muridarum drive arthritis.
Methods:
SKG, Il17a-deficient SKG, and BALB/c female mice were infected with C muridarum or C muridarum luciferase in the genitals. C muridarum dissemination was assessed by in vivo imaging or genomic DNA amplification. Macrophages were depleted using clodronate liposomes. Anti-tumor necrosis factor (anti-TNF) and anti-interleukin-23p19 (anti-IL-23p19) were administered after infection or arthritis onset. Gene expression of Hspa5, Tgtp1, Il23a, Il17a, Il12b, and Tnf was compared in SKG mice and BALB/c mice.
Results:
One week following infection with C muridarum, macrophages and neutrophils were observed to have infiltrated the uteri of mice and were also shown to have carried C muridarum DNA to the spleen. C muridarum load was higher in SKG mice than in BALB/c mice. Macrophage depletion was shown to reduce C muridarum load and prevent development of arthritis. Compared with BALB/c mice, expression of Il23a and Il17a was increased in the uterine and splenic neutrophils of SKG mice. The presence of anti-IL-23p19 during infection or Il17a deficiency suppressed arthritis. Tnf was overexpressed in the joints of SKG mice within 1 week postinfection, and persisted beyond the first week. TNF inhibition during infection or at arthritis onset suppressed the development of arthritis. Levels of endoplasmic reticulum stress were constitutively increased in the joints of SKG mice but were induced, in conjunction with immunity-related GTPase, by C muridarum infection in the uterus.
Conclusion:
C muridarum load is higher in SKG mice than in BALB/c mice. Whereas proinflammatory IL-23 produced by neutrophils contributes to the initiation of C muridarum-mediated ReA, macrophage depletion reduces C muridarum dissemination to other tissues, tissue burden, and the development of arthritis. TNF inhibition was also shown to suppress arthritis development. Our data suggest that enhanced bacterial dissemination in macrophages of SKG mice drives the TNF production needed for persistent arthritis.
Insights
Infection with Chlamydia muridarum causes reactive arthritis in SKG mice. Macrophages promote bacterial spread and TNF production, driving arthritis, while IL-23 from neutrophils initiates it.
Area of Science:
- Immunology
- Microbiology
- Pathology
Background:
- ZAP-70W163C BALB/c (SKG) mice are susceptible to reactive arthritis (ReA) after Chlamydia muridarum infection.
- Intracellular pathogens exploit stressed host cells for replication, suggesting myeloid cell involvement in arthritis pathogenesis.
Purpose of the Study:
- To investigate the role of myeloid cells, specifically macrophages, in driving Chlamydia muridarum-induced reactive arthritis in SKG mice.
- To elucidate the contribution of cytokines like IL-23 and TNF in the development of arthritis.
Main Methods:
- SKG and BALB/c mice were infected with Chlamydia muridarum.
- Macrophage depletion was induced using clodronate liposomes.
- In vivo imaging and DNA amplification assessed bacterial dissemination.
- Gene expression of key cytokines (Il23a, Il17a, Tnf) was analyzed.
- Inhibition of TNF and IL-23p19 was employed.
Main Results:
- Chlamydia muridarum load was higher in SKG mice, with macrophages and neutrophils infiltrating the uterus and carrying bacterial DNA to the spleen.
- Macrophage depletion reduced bacterial load and prevented arthritis development.
- Increased Il23a and Il17a expression was observed in SKG mice neutrophils, while Tnf was overexpressed in joints.
- Inhibition of IL-23p19 or TNF suppressed arthritis.
Conclusions:
- Proinflammatory IL-23 from neutrophils initiates Chlamydia muridarum-mediated ReA.
- Macrophages facilitate bacterial dissemination and drive TNF production, leading to persistent arthritis in SKG mice.
- Targeting macrophage-mediated bacterial spread and TNF production offers potential therapeutic strategies for reactive arthritis.
