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J. Biol. Chem., Vol. 282, Issue 36, 26409-26417, September 7, 2007

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A Novel Role of the Lumican Core Protein in Bacterial Lipopolysaccharide-induced Innate Immune Response^*

Feng Wu¹, Neeraj Vij¹, Luke Roberts, S. Lopez-Briones^¶, Sarah Joyce, and Shukti Chakravarti^||**2

From the Departments of Medicine, ^||Ophthalmology, ^**Cell Biology, ^¶Immunology, and Pediatrics, The Johns Hopkins School of Medicine, Baltimore, Maryland 21205

Lumican is an extracellular matrix protein modified as a proteoglycan in some tissues. The core protein with leucine-rich repeats, characteristic of the leucine-rich-repeat superfamily, binds collagen fibrils and regulates its structure. In addition, we believe that lumican sequestered in the pericellular matrix interacts with cell surface proteins for specific cellular functions. Here we show that bacterial lipopolysaccharide sensing by the Toll-like receptor 4 signaling pathway and innate immune response is regulated by lumican. Primary cultures of lumican-deficient (Lum^-/-) macrophages show impaired innate immune response to lipopolysaccharides with lower induction of tumor necrosis factor (TNF) and interleukin-6. Macrophage response to other pathogen-associated molecular patterns is not adversely affected by lumican deficiency, suggesting a specific role for the lumican core protein in the Toll-like receptor 4 pathway. An exogenous recombinant lumican core protein increases lipopolysaccharide-mediated TNF induction and partially rescues innate immune response in Lum^-/- macrophages. We further show that the core protein binds lipopolysaccharide. Immunoprecipitation of lumican from peritoneal lavage co-precipitates CD14, a cell surface lipopolysaccharide-binding protein that is involved in its presentation to Toll-like receptor 4. The Lum^-/- mice are hypo-responsive to lipopolysaccharide-induced septic shock, with poor induction of pro-inflammatory cytokines, TNF, and interleukins 1 and 6 in the serum. Taken together, the data indicates a novel role for lumican in the presentation of bacterial lipopolysaccharide to CD14 and host response to this bacterial endotoxin.

Received for publication, March 20, 2007 , and in revised form, June 22, 2007.

^* This study was supported by National Institutes of Health Grant EY11654 and the Crohn's and Colitis Foundation of America (to S. C.). 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 These authors contributed equally to this article.

² To whom correspondence should be addressed. Tel.: 410-502-7627; Fax: 410-614-4834; E-mail: schakra1{at}jhmi.edu.

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