Chlamydia-infected Macrophages mediate Interleukin-23 and Tumor Necrosis Factor-driven Reactive Arthritis in SKG Mice

• Published in: Arthritis & rheumatology (Hoboken, N.J.) N.J.), 2021-01
• Main Authors: Romand, Xavier, Liu, Xiao, Rahman, M Arifur, Bhuyan, Zaied Ahmed, Douillard, Claire, Arora Kedia, Reena, Stone, Nathan, Roest, Dominique, Chew, Zi Huai, Cameron, Amy J, Rehaume, Linda M, Bozon, Aurélie, Habib, Mohammed, Armitage, Charles W, Nguyen, Minh Vu Chuong, Favier, Bertrand, Beagley, Kenneth, Maurin, Max, Gaudin, Philippe, Thomas, Ranjeny, Wells, Timothy J, Baillet, Athan
• Format: Article
• Language: English
• ISSN: 2326-5205

ZAP-70 BALB/c (SKG) mice develop reactive arthritis (ReA) after Chlamydia muridarum (Cmu) infection. Since intracellular pathogens enhance their replicative fitness in stressed host cells, we examined how myeloid cells taking up Cmu drive arthritis. Female SKG, Il17a-deficient SKG and BALB/c mice were genitally infected with Cmu or Cmu Luciferase. Cmu dissemination was assessed by in vivo imaging or genomic DNA amplification. Macrophages were depleted using clodronate liposomes. Anti-TNF, anti-IL-23p19 were administered after infection or arthritis onset. Hspa5, Tgtp1, Il23a, Il17a, Il12b and Tnf expression was compared in SKG and BALB/c mice. One-week post infection, macrophages and neutrophils infiltrated the uterus; both carried Cmu DNA to the spleen. Cmu load was higher in SKG than BALB/c. Macrophage depletion reduced Cmu load and prevented arthritis. Compared with BALB/c, expression of Il23a and Il17a was increased in SKG uterine and splenic neutrophils. Anti-IL-23p19 during infection or Il17a deficiency suppressed arthritis. Tnf was over-expressed in SKG joints within one-week post infection and persisted. TNF inhibition during infection or at arthritis onset suppressed arthritis. Endoplasmic reticulum stress was constitutively increased in SKG joints but was induced, with immunity-related GTPase, by Cmu infection in uterus. The load of Cmu is higher in SKG than BALB/c mice. While proinflammatory IL-23 produced by neutrophils contributes to the initiation of Cmu-mediated ReA, macrophage depletion reduces Cmu dissemination to other tissues, tissue burden, and arthritis. TNF inhibition suppresses arthritis. Our data suggest that enhanced bacterial dissemination in SKG macrophages drives TNF production required for persistent arthritis.