title: Interleukin-10 regulates the inflammasome-driven augmentation of inflammatory arthritis and joint destruction.
abstract: BACKGROUND
  Activation 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.
  
  
  METHODS
  Antigen-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.
  
  
  RESULTS
  In 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.
  
  
  CONCLUSIONS
  These data provide a link between IL-10, synovial regulation of the NLRP3 inflammasome and the degree of bone erosions observed in inflammatory arthritis.
authors.forename: Claire J
authors.initials: CJ
authors.lastname: Greenhill
authors.forename: Gareth W
authors.initials: GW
authors.lastname: Jones
authors.forename: Mari A
authors.initials: MA
authors.lastname: Nowell
authors.forename: Zarabeth
authors.initials: Z
authors.lastname: Newton
authors.forename: Ann K
authors.initials: AK
authors.lastname: Harvey
authors.forename: Abdul N
authors.initials: AN
authors.lastname: Moideen
authors.forename: Fraser L
authors.initials: FL
authors.lastname: Collins
authors.forename: Anja C
authors.initials: AC
authors.lastname: Bloom
authors.forename: Rebecca C
authors.initials: RC
authors.lastname: Coll
authors.forename: Avril A B
authors.initials: AA
authors.lastname: Robertson
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Cooper
authors.forename: Marcela
authors.initials: M
authors.lastname: Rosas
authors.forename: Philip R
authors.initials: PR
authors.lastname: Taylor
authors.forename: Luke A
authors.initials: LA
authors.lastname: O'Neill
authors.forename: Ian R
authors.initials: IR
authors.lastname: Humphreys
authors.forename: Anwen S
authors.initials: AS
authors.lastname: Williams
authors.forename: Simon A
authors.initials: SA
authors.lastname: Jones
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology* / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000473:pathology; D002352:Carrier Proteins / Q000276:immunology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D007150:Immunohistochemistry; D058847:Inflammasomes / Q000276:immunology*; D016753:Interleukin-10 / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D002352:Carrier Proteins; C556062:IL10 protein, mouse; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D016753:Interleukin-10