Abstract
IntroductionActivation of the inflammasome has been implicated in the pathology of various autoinflammatory and autoimmune diseases. While the NLRP3 inflammasome has been linked to arthritis progression, little is known about its synovial regulation or contribution to joint histopathology. Regulators of inflammation activation, such as interleukin (IL)-10, may have the potential to limit the inflammasome-driven arthritic disease course and associated structural damage. Hence, we used IL-10-deficient (IL-10KO) mice to assess NLRP3 inflammasome-driven arthritic pathology.MethodsAntigen-induced arthritis (AIA) was established in IL-10KO mice and wild-type controls. Using histological and radiographic approaches together with quantitative real-time PCR of synovial mRNA studies, we explored the regulation of inflammasome components. These were combined with selective blocking agents and ex vivo investigative studies in osteoclast differentiation assays.ResultsIn AIA, IL-10KO mice display severe disease with increased histological and radiographic joint scores. Here, focal bone erosions were associated with increased tartrate-resistant acid phosphatase (TRAP)-positive cells and a localized expression of IL-1β. When compared to controls, IL-10KO synovium showed increased expression of Il1b, Il33 and NLRP3 inflammasome components. Synovial Nlrp3 and Casp1 expression further correlated with Acp5 (encoding TRAP), while neutralization of IL-10 receptor signaling in control mice caused increased expression of Nlrp3 and Casp1. In ex vivo osteoclast differentiation assays, addition of exogenous IL-10 or selective blockade of the NLRP3 inflammasome inhibited osteoclastogenesis.ConclusionsThese data provide a link between IL-10, synovial regulation of the NLRP3 inflammasome and the degree of bone erosions observed in inflammatory arthritis.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-014-0419-y) contains supplementary material, which is available to authorized users.
Highlights
Activation of the inflammasome has been implicated in the pathology of various autoinflammatory and autoimmune diseases
In ex vivo osteoclast differentiation assays, addition of exogenous IL-10 or selective blockade of the NLRP3 inflammasome inhibited osteoclastogenesis. These data provide a link between IL-10, synovial regulation of the NLRP3 inflammasome and the degree of bone erosions observed in inflammatory arthritis
Evaluation of synovial inflammation based on synovitis, cellular infiltrate, exudate and joint damage showed that histopathology was more prolonged in IL-10KO mice (Figure 1C)
Summary
Activation of the inflammasome has been implicated in the pathology of various autoinflammatory and autoimmune diseases. Pattern recognition receptors were initially characterized as sensors of microbial products of bacterial, fungal or viral infection These include the Toll-like receptors (TLR); nucleotide-binding domain and leucine-rich repeat containing receptors (NLR), Rig-I-like receptors (RLR) and C-type lectins [3,4]. Activation of these receptors promotes the inflammatory regulation of various interleukins, tumour necrosis family members and type-1 interferons [3]. They represent innate sensing mechanisms, which shape the adaptive immune response to chronic disease, allergy, cancer and infection. Interleukin-10 is abundantly expressed in synovial fluids of RA patients and has been linked with the control of bone resorption through inhibition of osteoclastogenesis in vitro [13,14,15]
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