期刊
JOURNAL OF AUTOIMMUNITY
卷 106, 期 -, 页码 -出版社
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jaut.2019.102336
关键词
Pentaxin 3; C1q; Pyroptosis; IL-6; Rheumatoid arthritis
类别
资金
- National Natural Science Foundation of China [81788104, 81630044, 81601432, 81550023, 81325019, 81771763, 81273312, 91542000, 81801633]
- Chinese Academy of Medical Science Innovation Fund for Medical Sciences [CIFMS2017-12M-1-008, 2016-12M-1-003, 2017-I2M-3-011, 2016-12M-1-008]
- Medical Epigenetics Research Center Fund, Chinese Academy of Medical Sciences [2017PT31035]
- Construction Project of National Traditional Chinese Medicine Clinical Research Base of SATCM
- Clinical Cooperative Project of Chinese and Western Medicine for Major and Knotty Diseases of SATCM
- Chinese Academy of Medical Sciences Young Medical Talent Award Fund [2018RC320005]
Excessive inflammatory cytokines play crucial roles in the pathogenesis of rheumatoid arthritis (RA), however, the underlying mechanism remains unclear. In this study, we demonstrated that pentaxin 3 (PTX3), an essential component of innate immunity, was elevated in RA and preferentially bound to CD14(+) monocytes. C1q promoted the binding and resulted in increased cell proliferation, activation and caspase-l-related late apoptotic cells (7-AAD(+) annexin V+), as well as enhanced release of inflammatory cytokines including TNF-alpha, IL-1 beta and IL-6. Serum from RA patients, compared with healthy controls, induced gasdermin D (GSDMD)-dependent pyroptosis in monocytes, and this ability was associated with disease activity. Moreover, PTX3 synergized with C1q to promote pyroptosis in RA-serum pre-incubated monocytes by coordinately enhancing NLRP3 inflammasome over-activation and inducing GSDMD cleavage, cell swelling with large bubbles, caspase-l-dependent cell death and inflammatory cytokine release including IL-6. On the other hand, IL-6 promoted PTX3 plus C1q-induced pyroptosis in both normal and RA serum pre-incubated monocytes. These findings collectively implicated an important role of IL-6 in driving PTX3 plus C1q-mediated pyroptosis in RA and shed lights on a potential new treatment strategy targeting pyroptosis-mediated persistent inflammatory cytokine release.
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