Destructive role of myeloid differentiation factor 88 and protective role of TRIF in interleukin-17–dependent arthritis in mice
Article first published online: 25 MAY 2012
Copyright © 2012 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 64, Issue 6, pages 1838–1847, June 2012
How to Cite
Abdollahi-Roodsaz, S., van de Loo, F. A. J., Koenders, M. I., Helsen, M. M., Walgreen, B., van den Bersselaar, L. A., Arntz, O. J., Takahashi, N., Joosten, L. A. B. and van den Berg, W. B. (2012), Destructive role of myeloid differentiation factor 88 and protective role of TRIF in interleukin-17–dependent arthritis in mice. Arthritis & Rheumatism, 64: 1838–1847. doi: 10.1002/art.34328
- Issue published online: 25 MAY 2012
- Article first published online: 25 MAY 2012
- Accepted manuscript online: 6 DEC 2011 04:04PM EST
- Manuscript Accepted: 1 DEC 2011
- Manuscript Received: 28 JUL 2011
- Dutch Arthritis Association. Grant Number: 03–1-301
- European BTCure IMI Program and performed within the framework of TI Pharma. Grant Number: Project D1-101
- Novartis AG
Increasing evidence indicates the involvement of Toll-like receptors (TLRs) in the progression of arthritis; however, the contribution of the two signaling pathways used by TLRs, which are mediated by myeloid differentiation factor 88 (MyD88) and TRIF, remains unclear. The objective of this study was to investigate the specific roles of MyD88 and TRIF in chronic experimental arthritis and the accompanying adaptive immune responses.
Chronic arthritis was induced in wild-type, MyD88−/−, and Triflps2 (TRIF−/−) mice by repetitive intraarticular injections of streptococcal cell wall (SCW) fragments. SCW-specific T cell and B cell responses, joint swelling, and histopathologic changes were analyzed during chronic arthritis.
Both MyD88 and TRIF pathways contributed to antigen-specific T cell proliferation and antibody production, with the MyD88 pathway playing the dominant role. The severity of joint swelling and synovial inflammation, as well as the histopathologic damage to cartilage and bone, was strongly dependent on MyD88 signaling, whereas TRIF was redundant. MyD88 signaling was critical for the development of pathogenic T cell response (i.e., interleukin-17 [IL-17] production) in response to SCW antigen. Interestingly, when the T cell–dependent phase was prolonged, TRIF signaling appeared to down-regulate bone erosion, an effect accompanied by an inhibitory effect on IL-17 production.
This study reveals a central role of MyD88 and a counterregulatory function of TRIF in T cell–driven arthritis. The findings provide a rationale for a pathway-specific interference in order to block the pathogenic features and to preserve or stimulate the beneficial aspects of TLR signaling.