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Veterans Affairs Medical Center, Department of Medicine, University of California San Diego, San Diego, CA 92161
Phagocyte ingestion of monosodium urate (MSU) crystals can induce proinflammatory responses and trigger acute gouty inflammation. Alternatively, the uptake of MSU crystals by mature macrophages can be noninflammatory and promote resolution of gouty inflammation. Macrophage activation by extracellular MSU crystals involves apparent recognition and ingestion mediated by TLR2 and TLR4, with subsequent intracellular recognition linked to caspase-1 activation and IL-1
processing driven by the NACHT-LRR-PYD-containing protein-3 inflammasome. In this study, we examined the potential role in gouty inflammation of CD14, a phagocyte-expressed pattern recognition receptor that functionally interacts with both TLR2 and TLR4. MSU crystals, but not latex beads, directly bound recombinant soluble (s) CD14 in vitro. CD14–/– bone marrow-derived macrophages (BMDMs) demonstrated unimpaired phagocytosis of MSU crystals but reduced p38 phosphorylation and 
90% less IL-1 and CXCL1 release. Attenuated MSU crystal-induced IL-1 release in CD14–/– BMDMs was mediated by decreased pro-IL-1 protein expression and additionally by decreased caspase-1 activation and IL-1 processing consistent with diminished NACHT-LRR-PYD-containing protein-3 inflammasome activation. Coating of MSU crystals with sCD14, but not sTLR2 or sTLR4, restored IL-1 and CXCL1 production in CD14–/– BMDMs in vitro. Gain of function of CD14 directly enhanced TLR4-mediated signaling in response to MSU crystals in transfected Chinese hamster ovary cells in vitro. Last, MSU crystal-induced leukocyte influx at 6 h was reduced by75%, and local induction of IL-1 decreased by >80% in CD14–/– mouse s.c. air pouches in vivo. We conclude that engagement of CD14 is a central determinant of the inflammatory potential of MSU crystals.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by grants from the Veterans Affairs Research Service and National Institutes of Health Grants AR049416 and HL077360.
2 Address correspondence and reprint requests to Dr. Ru Liu-Bryan, Veterans Affairs Medical Center, 111K, 3350 La Jolla Village Drive, San Diego, CA 92161. E-mail address: rliu{at}vapop.ucsd.edu
3 Abbreviations used in this paper: MSU, monosodium urate; ASC, adaptor protein apoptosis-associated speck-like protein containing a caspase recruitment domain; BMDM, bone marrow-derived macrophage; CHO, Chinese hamster ovary; s, soluble CD14; LRR, leucine-rich repeat; WT, wild type; NALP, NACHT-LRR-PYD-containing protein.
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