TY - JOUR
T1 - Mediation of Interleukin-23 and Tumor Necrosis Factor–Driven Reactive Arthritis by Chlamydia-Infected Macrophages in SKG Mice
AU - Romand, Xavier
AU - Liu, Xiao
AU - Rahman, M. Arifur
AU - Bhuyan, Zaied Ahmed
AU - Douillard, Claire
AU - Kedia, Reena Arora
AU - Stone, Nathan
AU - Roest, Dominique
AU - Chew, Zi Huai
AU - Cameron, Amy J.
AU - Rehaume, Linda M.
AU - Bozon, Aurélie
AU - Habib, Mohammed
AU - Armitage, Charles W.
AU - Nguyen, Minh Vu Chuong
AU - Favier, Bertrand
AU - Beagley, Kenneth
AU - Maurin, Max
AU - Gaudin, Philippe
AU - Thomas, Ranjeny
AU - Wells, Timothy J.
AU - Baillet, Athan
N1 - Funding Information:
We thank the SCIMI Microbiology Imaging Microscopy Facility at the TIMC-Imag University Grenoble Alpes (Grenoble, France) for technical advice and access to instruments.
Publisher Copyright:
© 2021, American College of Rheumatology
Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/7
Y1 - 2021/7
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85106731739&partnerID=8YFLogxK
U2 - 10.1002/art.41653
DO - 10.1002/art.41653
M3 - Article
C2 - 33452873
AN - SCOPUS:85106731739
SN - 2326-5191
VL - 73
SP - 1200
EP - 1210
JO - Arthritis and Rheumatology
JF - Arthritis and Rheumatology
IS - 7
ER -