Uveitis is a common extra-articular manifestation of several multisystem inflammatory diseases involving the joints. IL-1 is one of the best studied cytokines in arthritis, yet, in comparison, its potential to influence uveitis is poorly understood. Given the propensity of mice lacking IL-1Ra to exhibit features of systemic inflammation and spontaneous onset of arthritis, we tested the hypothesis that lack of IL-1Ra predisposes to uveitis. We found that the eye is less prone than joints to adverse effects from the loss of the IL-1Ra, and this observation is not altered by systemic LPS exposure. Interestingly, while deletion of IL-1R had no impact on EIU, IL-1Ra deficiency had a profound effect on the severity of EIU. This is consistent with the hypothesis that IL-1Ra has a critical regulatory role in preventing excessive IL-1 signalling in ocular inflammatory responses.
One contributing factor to the development of spontaneous arthritis in IL-1Ra KO mice is TLR4 activation by microbial flora.28
We verified previous reports28
that augmentation of TLR4 activation in IL-1Ra KO mice by a low dose of LPS at 7 weeks of age leads to exacerbated arthritis several weeks later. The eyes, however, remained unaffected despite the exacerbated arthritis. These observations are similar to the characteristics of patients with deficiency of the interleukin-1 receptor antagonist (DIRA), which is an autosomal recessive disease caused by an IL-1RN
which manifests as inflammation of the skin and joints. We are not aware of any reported eye involvement in these patients. The extent to which systemic inflammatory diseases affect the eye varies, and discordant mechanisms of disease in the eye versus joints have presented therapeutic challenges. For example, the tumour necrosis factor α (TNFα) inhibitor, etanercept, is used effectively for treating the arthritic symptoms in patients with ankylosing spondylitis, but it does not always improve uveitis in the same patients35
and will sometimes worsen uveitis.36
Although the presence of uveitis in several autoinflammatory diseases manifesting as arthritis suggests activation of common pathogenic mediators, such as IL-1β, in the eye and joint, our data would indicate that organ-specific responses must be considered.
The immunosuppressive milieu of the aqueous humour is thought to influence uveitogenesis37
by contributing to the immune privileged state of the eye.38
Resistance to the actions of IL-1β may be an underlying protective mechanism in the eye, and there are several possible mechanisms for regulating IL-1β actions. We demonstrated that IL-1R is expressed in eyes at concentrations comparable to susceptible joints and that it is functional because uveitis can be induced with exogenous IL-1β. Furthermore, the concentrations of IL-1β and IL-1α were increased in eyes with EIU. Given the presence of the receptor and the increased agonist concentrations, the finding that IL-1R deficiency did not significantly affect the severity of uveitis was somewhat surprising, but not completely unexpected. This observation is consistent with previous reports of EIU in rabbits,39
but is not in complete agreement with a report demonstrating that IL-1Ra overexpression in mouse eyes infected with a lentiviral expression vector suppresses EIU.40
Methods for the latter report differed substantially from ours; those authors used four times the amount of LPS and performed multiple LPS injections, suggesting their observation may be dependent on the high doses of LPS. Other cytokines, such TNFα and IL-8, may have somewhat redundant roles to IL-1 in EIU41,42
and reduce potential dependency on IL-1. Another aspect of IL-1 regulation is the production of negative regulators. We did not detect remarkably different expression of IL-1RII among the tissues. Of note, however, is that expression of the receptor variants, soluble IL-1RAcP and SIGIRR, which impede the activities of IL-1, was greater in the eye than in the knee or ankles and may contribute to the anti-inflammatory milieu controlling IL-1-mediated responses in the eye. Future investigation into how the actions of IL-1β may be inhibited by IL-1RAcP, SIGIRR or additional IL-1 family members such as IL-3743
will be important to our understanding of uveitis.
The final regulator we considered is the competitive inhibitor, IL-1Ra.44
Our data suggest that IL-1Ra successfully blocks the activity of IL-1 present in eyes during acute EIU, as mice deficient in IL-1Ra were extremely sensitive to local administration of LPS. We also noticed that IL-1Ra KO mice have an enhanced leucocyte trafficking response to intravitreally administered saline, which may reflect lack of inhibition of IL-1β released because of the injection injury. Collectively, these results underscore the importance of IL-1Ra in modulating ocular inflammation. Interestingly, differences in normal IL-1Ra concentrations among eyes, knees and ankles are inversely related to spontaneous disease predisposition in the IL-1Ra KO mice. Ankles, which had the highest basal concentrations of IL-1Ra, were the most inflamed in the IL-1Ra KO mice, whereas eyes, which had the lowest basal concentration, did not develop spontaneous inflammation. Perhaps ankles depend on IL-1Ra because they make more IL-1β, whereas eyes have less IL-1Ra because they make relatively low amounts of IL-1β and also have more IL-1RAcP and SIGIRR as discussed above. One caveat is that direct comparison of negative regulators and IL-1Ra concentrations among the organs is somewhat limited by variations in tissue composition and by the fact that we did not directly compare IL-1Ra concentrations in aqueous humour and synovial fluid because both fluids are extremely scant in the mouse. Nonetheless, the functional studies clearly support protective roles for IL-1Ra in arthritis and uveitis. Our results indicate that the actions of IL-1 appear to have a non-essential role in EIU because deficiency in IL-1R did not reduce inflammation. We would like to emphasise that the converse, however, is not true. The importance of proper regulation of IL-1 signalling is clearly evidenced by the severely exacerbated EIU that occurs in IL-1Ra KO mice when the effects of IL-1 are amplified. The latter would presumably relate to diseases such as Behçet’s wherein dysregulation of IL-1 is implicated. The efficacy of anti-IL-1 therapy of uveitis in patients with arthritis should be informative regarding pathogenesis of particular diseases. Interestingly, a preliminary trial suggests marked benefit of anti-IL-1 therapy in treatment of uveitis in patients with Behçet’s disease.1,2
Despite a strong link between uveitis and several arthritic diseases, few studies have attempted to explain the common coexistence of inflammation in the two organ systems. Here we sought to elucidate how dysregulation of the actions of a single cytokine (ie, IL-1β) affects experimental models of uveitis and arthritis. Our findings underscore the complexity of the determinants that influence the eye’s susceptibility to uveitis and show differences not only between the eye and joints but between the knee and the ankle. Collectively, the data indicate the importance of proper regulation of the actions of IL-1 in the eye, as worsened uveitis ensues in the absence of IL-1Ra.