title: SIGIRR/TIR-8 is an inhibitor of Toll-like receptor signaling in primary human cells and regulates inflammation in models of rheumatoid arthritis.
abstract: OBJECTIVE
  Single-immunoglobulin interleukin-1 receptor-related (SIGIRR), which is also known as Toll/interleukin-1 receptor 8 (TIR-8), is a member of the TIR domain-containing family of receptors and was first characterized as an inhibitor of interleukin-1 receptor (IL-1R) and Toll-like receptor (TLR) signaling. In the Dextran sulfate sodium-induced colitis model, SIGIRR(-/-) mice were shown to have increased inflammation and to be more susceptible to endotoxin challenge. Increasing evidence implicates TLR and IL-1R signaling in the pathology of rheumatoid arthritis (RA). Therefore, the purpose of this study was to investigate the involvement of SIGIRR in regulating inflammation in disease-relevant models.
  
  
  METHODS
  Primary human monocyte-derived macrophages and dendritic cells (DCs) were used to overexpress SIGIRR as well as to knock down endogenously expressed SIGIRR using small interfering RNAs. SIGIRR was also overexpressed in synovial cells derived from RA patients. To investigate the role of SIGIRR in vivo, zymosan-induced arthritis (ZIA) and collagen antibody-induced arthritis (CAIA) were induced in SIGIRR-knockout mice.
  
  
  RESULTS
  SIGIRR overexpression inhibited TLR-induced cytokine production in macrophages and DCs, while SIGIRR knockdown resulted in increased cytokine production following TLR stimulation. Moreover, SIGIRR overexpression inhibited the spontaneous release of cytokines by human RA synovial cells. The role of SIGIRR as an inhibitor of inflammation was confirmed in vivo, since SIGIRR(-/-) mice developed a more severe disease in both the ZIA and CAIA models.
  
  
  CONCLUSIONS
  Our study is the first to show the expression pattern and function of SIGIRR in primary human cells. Furthermore, this investigation defines the role of SIGIRR in disease-relevant cell types and demonstrates that SIGIRR is a potential therapeutic target for RA.
authors.affiliation: Imperial College London, London, UK.
authors.forename: Stefan K
authors.initials: SK
authors.lastname: Drexler
authors.forename: Philip
authors.initials: P
authors.lastname: Kong
authors.forename: Julia
authors.initials: J
authors.lastname: Inglis
authors.forename: Richard O
authors.initials: RO
authors.lastname: Williams
authors.forename: Cecilia
authors.initials: C
authors.lastname: Garlanda
authors.forename: Alberto
authors.initials: A
authors.lastname: Mantovani
authors.forename: Amir S
authors.initials: AS
authors.lastname: Yazdi
authors.forename: Fionula
authors.initials: F
authors.lastname: Brennan
authors.forename: Marc
authors.initials: M
authors.lastname: Feldmann
authors.forename: Brian M J
authors.initials: BM
authors.lastname: Foxwell
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015153:Blotting, Western; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D018014:Gene Transfer Techniques; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D034622:RNA Interference; D034741:RNA, Small Interfering; D017472:Receptors, Interleukin-1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D051193:Toll-Like Receptors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: D034741:RNA, Small Interfering; D017472:Receptors, Interleukin-1; D051193:Toll-Like Receptors; C546891:SIGIRR protein, human