• Arthritis and rheumatism · Sep 2005

    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.

    • Ru Liu-Bryan, Peter Scott, Anya Sydlaske, David M Rose, and Robert Terkeltaub.
    • VA Medical Center, University of California, San Diego 92161, USA. rliu@vapop.ucsd.edu
    • Arthritis Rheum. 2005 Sep 1; 52 (9): 2936-46.

    ObjectiveIn 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.MethodsWe 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.ResultsTLR-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.ConclusionThe 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.

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