Abstract
Lumican is an extracellular protein that associates with CD14 on the surface of macrophages and neutrophils, and promotes CD14-TLR4 mediated response to bacterial lipopolysaccharides (LPS). Lumican-deficient (Lum −/−) mice and macrophages are impaired in TLR4 signals; raising the possibility that lumican may regulate host response to live bacterial infections. In a recent study we showed that in vitro Lum −/− macrophages are impaired in phagocytosis of gram-negative bacteria and in a lung infection model the Lum −/− mice showed poor survival. The cornea is an immune privileged barrier tissue that relies primarily on innate immunity to protect against ocular infections. Lumican is a major component of the cornea, yet its role in counteracting live bacteria in the cornea remains poorly understood. Here we investigated Pseudomonas aeruginosa infections of the cornea in Lum −/− mice. By flow cytometry we found that 24 hours after infection macrophage and neutrophil counts were lower in the cornea of Lum −/− mice compared to wild types. Infected Lum −/− corneas showed lower levels of the leukocyte chemoattractant CXCL1 by 24–48 hours of infection, and increased bacterial counts up to 5 days after infection, compared to Lum+/− mice. The pro-inflammatory cytokine TNF-α was comparably low 24 hours after infection, but significantly higher in the Lum −/− compared to Lum +/− infected corneas by 2–5 days after infection. Taken together, the results indicate that lumican facilitates development of an innate immune response at the earlier stages of infection and lumican deficiency leads to poor bacterial clearance and resolution of corneal inflammation at a later stage.
Highlights
Lumican is an extracellular matrix proteoglycan that is known to regulate collagen fibril structure and corneal transparency [1,2]
LPS sensing is mediated by toll-like receptor (TLR) 4; the sequence of events upon LPS encounter involves its binding to LBP (LPS-binding protein), subsequent binding to CD14, a glycosylphosphatidyl inositol linked adaptor protein, which delivers LPS to MD-2, a soluble protein, complexed to TLR4, causing a conformational change in TLR4, recruitment of cytoplasmic adaptor proteins and signal transduction [8]
We identified binding between lumican and CD14, and determined that recombinant lumican could rescue LPS signaling in Lum2/2 peritoneal macrophages [3,5]
Summary
Lumican is an extracellular matrix proteoglycan that is known to regulate collagen fibril structure and corneal transparency [1,2]. We found that lumican interacts with bacterial lipopolysaccharide (LPS) endotoxins and facilitates host response to LPS. Mice deficient in lumican (Lum2/2) were hypo responsive to LPS and compared to wild types showed improved survival in a septic shock model induced by intraperitoneal injection of LPS [3]. We identified binding between lumican and CD14, and determined that recombinant lumican could rescue LPS signaling in Lum2/2 peritoneal macrophages [3,5]. Peritoneal macrophages from lumican knockout mice were impaired in in vitro phagocytosis of gram-negative bacteria in a CD14-dependent mechanism. These LPS signaling deficiencies raise the possibility that challenged with live bacteria, the lumican-null mice may manifest specific host defense susceptibilities
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