The Role of Lumican in the cornea

Johns Hopkins University, Baltimore MD

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Abstract

The avascular cornea is a protective barrier with intact innate immune, but restricted adaptive immune response to assure unrestricted vision. Surgery, injury and infection of the cornea can disrupt this balance between innate and adaptive immune response leading to intense inflammation and loss of vision. We found lumican, an abundant extracellular matrixJECM) stromal proteoglycan, to regulate corneal immune functions. Mice, deficient in lumican (Lum ), are hypo responsive to bacterial lipopolysacharide endotoxin (LPS), and produce lower amounts of proinflammatory cytokines. More importantly, in LPS-induced corneal keratitis, the Lumv'mice show reduced neutrophil influx early, but delayed healing at the late stage. Lumican itself binds LPS and CD 14, the cell surface adaptor protein that transfers LPS to toll-like receptor 4, a trans-membrane LPS receptor. Thus, innate immune response to LPS is impaired in our Lumv" mice. Lumican also binds FasL and TGFp, and in the Lumv" mice these pathways are disrupted. The Fas-FasL mediated apoptosis and TGFp signaling in the cornea help to maintain an immunosuppressive environment for immune privilege. Our overarching hypothesis is that in the cornea lumican promotes early innate immune response, but provides an immunosuppressive microenvironment to restrict adaptive immunogenic mechanisms to maintain immune privilege. The following aims will investigate lumican in corneal inflammation and the adaptive immune response to corneal allografts. 1) Test if lumican regulates corneal inflammation and immune privilege such that Lumv" corneal allografts have decreased survival. Test if lumican regulates bone marrow cell (BMC) functions directly by evaluating allograft success in Lum+A and Lumv" BMC chimera hosts. 2) Test if lumican promotes corneal innate immune response via the LPS-specific CD 14- TLR4 pathway, a) in cell culture by assessing the ability of recombinant lumican (rLum) to rescue LPSinduction of TNFa in Lumv" macrophages also lacking CD14, and b) by comparing LPS-induced keratitis in Lum+A and Lumv" BMC chimeras in a CD14-null background. 3) Characterize the lumican-CD14 interactions. After testing the ability of lumican, its derivatives or anti-lumican antibodies to induce innate immune response in macrophage culture, test their potential in the treatment of LPS-induced keratitis. This study will elucidate a novel link between the stromal ECM and corneal immune functions and lead to the development of therapeutic lumican-products to alleviate detrimental inflammatory responses in the cornea, a major focus of the National Eye Institute.