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

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 1

Attenuated bone erosion and Treg accumulation with early IL-1β blockade.

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Attenuated bone erosion and Treg accumulation with early IL-1β blockade....
(A–I) Il1rn–/– mice were treated with anti–IL-1β or isotype-matched IgG (n = 6) (5 mg/kg i.p. once per week) for 2 weeks either at the weaning (early treatment, n = 6) or 14 days after (late treatment n = 6). (A) Experimental scheme detailing administration time of i.p. anti–IL-1β. (B) Arthritis score (0–3/per paw, 0–12 total) and ankle and wrist thickening measured by calipers were followed for 35 days after arthritis weaning. (C) H&E staining of representative knee joints. Il1rn–/– joints from mice treated with isotype control or late anti–IL-1β display cellular infiltration (I), synovial hyperplasia (H), pannus formation (P), and bone and cartilage erosion (E). Scale bars: 1 μm. (D) Histological evaluation of knee joints from Il1rn–/– mice treated with anti–IL-1β (early treatment n = 4, late treatment n = 4) or isotype-matched IgG (n = 4). (E) High-resolution micro-computed tomography (μCT) imaging of knees from WT and Il1rn–/– mice treated with anti–IL-1β (n = 10 per group) or isotype-matched IgG (n = 4). (F) Bone erosion score by μCT (0–3 total). (G) Cytokine expression by CD3+Foxp3eGFP+ cells from synovial tissue by flow cytometry. (H and I) Frequency of CD3+Foxp3eGFP+ cells expressing IFN-γ and IL-17A. (J) Frequency of Foxp3eGFP+ cells among CD3+ cells in joint tissue. Data are expressed as mean ± SEM. Statistical significance was determined using 3-way ANOVA (B) or 1-way ANOVA (D, F, G, and I).