IL-1-driven cartilage and bone destruction are dependent on Toll-like receptor (TLR) 4, but not TLR2

Rheumatoid arthritis (RA) is an autoimmune disease characterized by systemic, chronic joint inflammation. In spite of great efforts, the etiology of RA has not been completely elucidated to date. Toll-like receptors (TLRs) belong to the family of pattern recognition receptors and are involved in both innate and adaptive immune responses against microorganisms via recognition of pathogen-associated molecular patterns. In addition, TLRs have been reported to recognize several endogenous ligands, which are generated under stress conditions and cartilage damage. Triggering of TLRs results in the release of various proinflammatory cytokines such as IL-1β and tumor necrosis factor alpha. IL-1β is one of the crucial cytokines in the pathogenesis of RA and is involved in Th1-mediated processes and cartilage and bone destruction. Therefore, TLRs may potentially be involved in either initiation or chronicity of arthritis.

To study the contribution of TLR2 and TLR4 in IL-1β-driven joint inflammation, cartilage destruction and bone erosion.

C57BL/6 wild-type (WT), BL/6 TLR2 knockout (KO), C57BL/10 WT and BL/10 TLR4 KO mice were intra-articularly injected with 3 × 10⁶ PFU mouse IL-1β adenoviral vector (AdmIL-1β) or control vector (Ad5del70-3). Inflammatory cell infiltration, cartilage proteoglycan (PG) depletion and cartilage and bone destruction were microscopically examined 7 days after virus injection.

Prolonged expression of mIL-1β in mice knee joints induced a severe arthritis in WT animals, exhibiting pathophysiologic changes resembling those in human RA. High amounts of inflammatory cells, predominantly polymorphonuclear cells, were present in the knee joint cavities of both WT and KO mice. Severe PG depletion, cartilage destruction and bone erosion were observed in WT mice, which did not differ from those in TLR2-deficient mice. Interestingly, in TLR4-deficient mice, cartilage PG depletion and destruction were significantly reduced. TLR4 KO mice showed also a marked reduction in bone erosion compared with WT mice, although this reduction was not significant.

These data strongly suggest that TLR4 is involved in IL-1β-driven pathologic processes. Both cartilage and bone destruction were reduced in TLR4 KO mice, although joint inflammation was comparable with WT mice. This indicates the involvement of potential TLR4 ligands, generated by IL-1β-induced cartilage degradation, in chronic RA. Our data point out that TLR4 may be a novel therapeutic target in the treatment of RA.