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  • Title: Role of the leucine-rich repeat domain of cryopyrin/NALP3 in monosodium urate crystal-induced inflammation in mice.
    Author: Hoffman HM, Scott P, Mueller JL, Misaghi A, Stevens S, Yancopoulos GD, Murphy A, Valenzuela DM, Liu-Bryan R.
    Journal: Arthritis Rheum; 2010 Jul; 62(7):2170-9. PubMed ID: 20506351.
    Abstract:
    OBJECTIVE: The mechanism by which monosodium urate monohydrate (MSU) crystals intracellularly activate the cryopyrin inflammasome is unknown. The aim of this study was to use a mouse molecular genetics-based approach to test whether the leucine-rich repeat (LRR) domain of cryopyrin is required for MSU crystal-induced inflammation. METHODS: Cryopyrin-knockout lacZ (Cryo(-Z/-Z)) mice and mice with the cryopyrin LRR domain deleted and fused to the lacZ reporter (Cryo(DeltaLRR Z/DeltaLRR Z)) were generated using bacterial artificial chromosome-based targeting vectors, which allow for large genomic deletions. Bone marrow-derived macrophages from Cryo(DeltaLRR Z/DeltaLRR Z) mice, Cryo(-Z/-Z) mice, and congenic wild-type (WT) mice were challenged with endotoxin-free MSU crystals under serum-free conditions. Phagocytosis and cytokine expression were assessed by flow cytometry and enzyme-linked immunosorbent assay. MSU crystals also were injected into mouse synovial-like subcutaneous air pouches. The in vivo inflammatory responses were examined. RESULTS: Release of interleukin-1beta (IL-1beta), but not CXCL1 and tumor necrosis factor alpha, was impaired in Cryo(DeltaLRR Z/DeltaLRR Z) and Cryo(-Z/-Z) mouse bone marrow-derived macrophages compared with WT mouse bone marrow-derived macrophages in response to not only MSU crystals but also other known stimuli that activate the cryopyrin inflammasome. In addition, a comparable percentage of MSU crystals taken up by each type of bone marrow-derived macrophage was observed. Moreover, total leukocyte infiltration in the air pouch and IL-1beta production were attenuated in Cryo(-Z/-Z) and Cryo(DeltaLRR Z/DeltaLRR Z) mice at 6 hours postinjection of MSU crystals compared with WT mice. CONCLUSION: MSU crystal-induced inflammatory responses were comparably attenuated both in vitro and in vivo in Cryo(DeltaLRR Z/DeltaLRR Z) and Cryo(-Z/-Z) mice. Hence, the LRR domain of cryopyrin plays a role in mediating MSU crystal-induced inflammation in this model.
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