Background
NOD2 is the genetic cause of Blau syndrome, an autoinflammatory disease that manifests as coincident uveitis and arthritis. Since dysregulation of IL-1 signalling is considered a pathogenic mechanism in a number of related autoinflammatory conditions, we examined the extent to which unimpeded interleukin (IL)-1 signalling influences NOD2-dependent inflammation of the eye versus the joint.
Conclusions
Our findings highlight the complexity of NOD2 activation and IL-1 signalling effects that can be compounded by local environmental factors of the target organ. These observations may impact how we understand the molecular mechanisms by which NOD2 influences inflammation of the eye versus joint, and consequently, treatment options for uveitis versus arthritis.
Methods
Mice deficient for IL-1R antagonist (IL-1Ra) were administered the NOD2 agonist muramyl dipeptide (MDP) by systemic (intraperitoneal) or local (intraocular and/or intra-articular) injections. NOD2-deficient mice received an intraocular injection of recombinant IL-1β. Uveitis was evaluated by intravital videomicroscopy and histopathology, and arthritis was assessed by near-infrared imaging and histopathology. Ocular levels of IL-1α, IL-1β and IL-1Ra were quantified by enzyme-linked immunosorbent assay.
Results
IL-1Ra deficiency did not render mice more responsive to systemic exposure of MDP. Despite the increased production of IL-1R agonists IL-1α and IL-1β in response to intraocular injection of MDP, deficiency in IL-1Ra did not predispose mice to MDP-triggered uveitis, albeit intravascular cell rolling and adherence were exacerbated. NOD2 expression was dispensable for the potential of IL-1 to elicit uveitis. However, we find that IL-1Ra does play an important protective role in arthritis induced locally by MDP injection in the joint. Conclusions: Our findings highlight the complexity of NOD2 activation and IL-1 signalling effects that can be compounded by local environmental factors of the target organ. These observations may impact how we understand the molecular mechanisms by which NOD2 influences inflammation of the eye versus joint, and consequently, treatment options for uveitis versus arthritis.