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IL-1β–driven osteoclastogenic Tregs accelerate bone erosion in arthritis
Anaïs Levescot, … , Julia F. Charles, Peter A. Nigrovic
Anaïs Levescot, … , Julia F. Charles, Peter A. Nigrovic
Published August 3, 2021
Citation Information: J Clin Invest. 2021;131(18):e141008. https://doi.org/10.1172/JCI141008.
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Research Article Autoimmunity Inflammation

IL-1β–driven osteoclastogenic Tregs accelerate bone erosion in arthritis

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Abstract

IL-1β is a proinflammatory mediator with roles in innate and adaptive immunity. Here we show that IL-1β contributes to autoimmune arthritis by inducing osteoclastogenic capacity in Tregs. Using mice with joint inflammation arising through deficiency of the IL-1 receptor antagonist (Il1rn–/–), we observed that IL-1β blockade attenuated disease more effectively in early arthritis than in established arthritis, especially with respect to bone erosion. Protection was accompanied by a reduction in synovial CD4+Foxp3+ Tregs that displayed preserved suppressive capacity and aerobic metabolism but aberrant expression of RANKL and a striking capacity to drive RANKL-dependent osteoclast differentiation. Both Il1rn–/– Tregs and wild-type Tregs differentiated with IL-1β accelerated bone erosion upon adoptive transfer. Human Tregs exhibited analogous differentiation, and corresponding RANKLhiFoxp3+ T cells could be identified in rheumatoid arthritis synovial tissue. Together, these findings identify IL-1β–induced osteoclastogenic Tregs as a contributor to bone erosion in arthritis.

Authors

Anaïs Levescot, Margaret H. Chang, Julia Schnell, Nathan Nelson-Maney, Jing Yan, Marta Martínez-Bonet, Ricardo Grieshaber-Bouyer, Pui Y. Lee, Kevin Wei, Rachel B. Blaustein, Allyn Morris, Alexandra Wactor, Yoichiro Iwakura, James A. Lederer, Deepak A. Rao, Julia F. Charles, Peter A. Nigrovic

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Figure 2

Il1rn–/– Tregs are present and highly suppressive.

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Il1rn–/– Tregs are present and highly suppressive.
(A) CCR6 and CD39 ex...
(A) CCR6 and CD39 expression on CD4+Foxp3+ T cells from WT and Il1rn–/– mouse synovial tissue by flow cytometry (n = 6). (B) Frequency of CD39 and CCR6 on Foxp3+ T cells from synovial tissue. (C–H) Il1rn–/– mice were treated with anti–IL-1β (αIL-1β) or isotype-matched IgG (n = 5) (5 mg/kg i.p. once per week) for 2 weeks either at weaning (early treatment, n = 5) or 14 days after (late treatment n = 5). (C) Foxp3 and IL-17 expression by CD4+ T cells from synovial tissue harvested 35 days after weaning by flow cytometry (n = 5). (D) Frequency of CD4+Foxp3– and CD4+Foxp3+ cells expressing IL-17 from synovial tissue harvested 35 days after weaning (n = 5 per group). (E) Foxp3 and RORγt expression by CD4+ cells from synovial tissue by flow cytometry (n = 5, late treatment n = 3). (F) Frequency of CD4+Foxp3– and CD4+Foxp3+ cells expressing RORγt (n = 5 per group, late treatment n = 3). (G and H) Foxp3+ cells from WT mice or Il1rn–/– mice treated with anti–IL-1β or isotype-matched IgG were cocultured with WT Foxp3– cells (n = 5 per group). (G) Proliferation of CD3+Foxp3– cells following 72 hours of coculture. (H) Percentage of divided WT CD3+Foxp3– cells. (I and J) Foxp3+ cells from WT mice or Il1rn–/– mice treated with anti–IL-1β or isotype-matched IgG were cocultured with Foxp3eGFP– cells from a donor of the same strain (n = 5 per group). (I) Foxp3– cell proliferation following 72 hours of coculture. (J) Percentage of divided WT Foxp3– cells. Data are expressed as mean ± SEM. Statistical significance was determined using 1-way ANOVA (B, D, F, and H).

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