PMID- 16142712
OWN - NLM
STAT- MEDLINE
DCOM- 20051101
LR  - 20220408
IS  - 0004-3591 (Print)
IS  - 0004-3591 (Linking)
VI  - 52
IP  - 9
DP  - 2005 Sep
TI  - Innate immunity conferred by Toll-like receptors 2 and 4 and myeloid 
      differentiation factor 88 expression is pivotal to monosodium urate monohydrate 
      crystal-induced inflammation.
PG  - 2936-46
AB  - OBJECTIVE: In gout, incompletely defined molecular factors alter recognition of 
      dormant articular and bursal monosodium urate monohydrate (MSU) crystal deposits, 
      thereby inducing self-limiting bouts of characteristically severe neutrophilic 
      inflammation. To define primary determinants of cellular recognition, uptake, and 
      inflammatory responses to MSU crystals, we conducted a study to test the role of 
      Toll-like receptor 2 (TLR-2), TLR-4, and the cytosolic TLR adapter protein 
      myeloid differentiation factor 88 (MyD88), which are centrally involved in innate 
      immune recognition of microbial pathogens. METHODS: We isolated bone 
      marrow-derived macrophages (BMDMs) in TLR-2-/-, TLR-4-/-, MyD88-/-, and congenic 
      wild-type mice, and assessed phagocytosis and cytokine expression in response to 
      endotoxin-free MSU crystals under serum-free conditions. MSU crystals also were 
      injected into mouse synovium-like subcutaneous air pouches. RESULTS: TLR-2-/-, 
      TLR-4-/-, and MyD88-/- BMDMs demonstrated impaired uptake of MSU crystals in 
      vitro. MSU crystal-induced production of interleukin-1beta (IL-1beta), tumor 
      necrosis factor alpha, keratinocyte-derived cytokine/growth-related oncogene 
      alpha, and transforming growth factor beta1 also were significantly suppressed in 
      TLR-2-/- and TLR-4-/- BMDMs and were blunted in MyD88-/- BMDMs in vitro. 
      Neutrophil influx and local induction of IL-1beta in subcutaneous air pouches 
      were suppressed 6 hours after injection of MSU crystals in TLR-2-/- and TLR-4-/- 
      mice and were attenuated in MyD88-/- mice. CONCLUSION: The murine host requires 
      TLR-2, TLR-4, and MyD88 for macrophage activation and development of full-blown 
      neutrophilic, air pouch inflammation in response to MSU crystals. Our findings 
      implicate innate immune cellular recognition of naked MSU crystals by specific 
      TLRs as a major factor in determining the inflammatory potential of MSU crystal 
      deposits and the course of gouty arthritis.
FAU - Liu-Bryan, Ru
AU  - Liu-Bryan R
AD  - VA Medical Center, University of California, San Diego 92161, USA. 
      rliu@vapop.ucsd.edu
FAU - Scott, Peter
AU  - Scott P
FAU - Sydlaske, Anya
AU  - Sydlaske A
FAU - Rose, David M
AU  - Rose DM
FAU - Terkeltaub, Robert
AU  - Terkeltaub R
LA  - eng
GR  - AR-049416/AR/NIAMS NIH HHS/United States
GR  - HL-077360/HL/NHLBI NIH HHS/United States
GR  - P30-AR-43360/AR/NIAMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Arthritis Rheum
JT  - Arthritis and rheumatism
JID - 0370605
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Antigens, Differentiation)
RN  - 0 (Cytokines)
RN  - 0 (Myd88 protein, mouse)
RN  - 0 (Myeloid Differentiation Factor 88)
RN  - 0 (Receptors, Immunologic)
RN  - 0 (Tlr2 protein, mouse)
RN  - 0 (Tlr4 protein, mouse)
RN  - 0 (Toll-Like Receptor 2)
RN  - 0 (Toll-Like Receptor 4)
RN  - 268B43MJ25 (Uric Acid)
SB  - IM
MH  - Adaptor Proteins, Signal Transducing
MH  - Animals
MH  - Antigens, Differentiation/genetics/*metabolism
MH  - *Arthritis, Gouty/genetics/immunology/metabolism
MH  - Bone Marrow Cells/drug effects/metabolism
MH  - Cytokines/metabolism
MH  - Disease Models, Animal
MH  - Immunity, Innate/*immunology
MH  - Macrophages/drug effects/metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Myeloid Differentiation Factor 88
MH  - Phagocytosis/drug effects
MH  - Receptors, Immunologic/genetics/*metabolism
MH  - Specific Pathogen-Free Organisms
MH  - Toll-Like Receptor 2
MH  - Toll-Like Receptor 4
MH  - *Uric Acid/immunology/toxicity
EDAT- 2005/09/06 09:00
MHDA- 2005/11/03 09:00
CRDT- 2005/09/06 09:00
PHST- 2005/09/06 09:00 [pubmed]
PHST- 2005/11/03 09:00 [medline]
PHST- 2005/09/06 09:00 [entrez]
AID - 10.1002/art.21238 [doi]
PST - ppublish
SO  - Arthritis Rheum. 2005 Sep;52(9):2936-46. doi: 10.1002/art.21238.