期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 131, 期 18, 页码 -出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI141008
关键词
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资金
- Joint Biology Consortium Microgrant (parent grant NIH) [P30AR070253]
- NIH [P30AR070253, K08 AR062590, T32AI007512, K12HD052896, K08 AR074562]
- Rheumatology Research Foundation Scientist Development Award
- PROMOS scholarship from the German Academic Exchange Service
- Burroughs Wellcome Fund Career Award for Medical Scientists
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) [K08 AR072791]
- NIAMS [P30AR070253, R01AR065538, R01AR075906, R01AR073201, R21AR076630]
- National Heart, Lung, and Blood Institute [R21HL150575]
- Lupus Research Alliance Target Identification in Lupus Grant
- Fundacion Bechara
- Arbuckle Family Fund for Arthritis Research
- Novartis
- Boehringer Ingelheim Fonds MD Fellowship
- Rheumatology Research Foundation K Supplement Award
- Samara Jan Turkel Clinical Center for Pediatric Autoimmune Diseases at Boston Children's Hospital
The study reveals that IL-1 beta contributes to autoimmune arthritis by inducing osteoclastogenic capacity in Tregs, leading to bone erosion.
IL-1 beta is a proinflammatory mediator with roles in innate and adaptive immunity. Here we show that IL-1 beta 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-1 beta 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-1 beta accelerated bone erosion upon adoptive transfer. Human Tregs exhibited analogous differentiation, and corresponding RANKL(hi)Foxp3(+) T cells could be identified in rheumatoid arthritis synovial tissue. Together, these findings identify IL-1 beta-induced osteoclastogenic Tregs as a contributor to bone erosion in arthritis.
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