Extracellular matrix protein lumican promotes clearance and resolution of Pseudomonas aeruginosa keratitis in a mouse model.
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 invitro 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.
Department of Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.
Hanjuan
H
Shao
Sherri-Gae
SG
Scott
Chiaki
C
Nakata
Abdel R
AR
Hamad
Shukti
S
Chakravarti
D000818:Animals; D001483:Base Sequence; D011508:Chondroitin Sulfate Proteoglycans / Q000235:genetics / Q000502:physiology*; D017931:DNA Primers; D004797:Enzyme-Linked Immunosorbent Assay; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000502:physiology*; D005434:Flow Cytometry; D007632:Keratan Sulfate / Q000235:genetics / Q000502:physiology*; D007634:Keratitis / Q000382:microbiology / Q000503:physiopathology / Q000517:prevention & control*; D008070:Lipopolysaccharides / Q000633:toxicity; D000071234:Lumican; D051379:Mice; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction; D011552:Pseudomonas Infections / Q000382:microbiology / Q000503:physiopathology / Q000517:prevention & control*; D011550:Pseudomonas aeruginosa / Q000302:isolation & purification*
D011508:Chondroitin Sulfate Proteoglycans; D017931:DNA Primers; D016326:Extracellular Matrix Proteins; D008070:Lipopolysaccharides; C000604307:Lum protein, mouse; D000071234:Lumican; D007632:Keratan Sulfate