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J Biol Chem. 2012 Oct 19;287(43):35860-72. doi: 10.1074/jbc.M112.380550. Epub 2012 Aug 3.

Extracellular matrix lumican promotes bacterial phagocytosis, and Lum-/- mice show increased Pseudomonas aeruginosa lung infection severity.

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1
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.

Erratum in

  • J Biol Chem. 2014 Dec 5;289(49):33874.

Abstract

Phagocytosis is central to bacterial clearance, but the exact mechanism is incompletely understood. Here, we show a novel and critical role for lumican, the connective tissue extracellular matrix small leucine-rich repeat proteoglycan, in CD14-mediated bacterial phagocytosis. In Psuedomonas aeruginosa lung infections, lumican-deficient (Lum(-/-)) mice failed to clear the bacterium from lungs, tissues, and showed a dramatic increase in mortality. In vitro, phagocytosis of nonopsonized gram-negative Escherichia coli and P. aeruginosa was inhibited in Lum(-/-) peritoneal macrophages (MΦs). Lumican co-localized with CD14, CD18, and bacteria on Lum(+/+) MΦ surfaces. Using two different P. aeruginosa strains that require host CD14 (808) or CD18/CR3 (P1) for phagocytosis, we showed that lumican has a larger role in CD14-mediated phagocytosis. Recombinant lumican (rLum) restored phagocytosis in Lum(-/-) MΦs. Surface plasmon resonance showed specific binding of rLum to CD14 (K(A) = 2.15 × 10(6) M(-1)), whereas rLumY20A, and not rLumY21A, where a tyrosine in each was replaced with an alanine, showed 60-fold decreased binding. The rLumY20A variant also failed to restore phagocytosis in Lum(-/-) MΦs, indicating Tyr-20 to be functionally important. Thus, in addition to a structural role in connective tissues, lumican has a major protective role in gram-negative bacterial infections, a novel function for small leucine-rich repeat proteoglycans.

PMID:
22865855
PMCID:
PMC3476255
DOI:
10.1074/jbc.M112.380550
[Indexed for MEDLINE]
Free PMC Article
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