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