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

Publication Type:

Journal Article

Source:

The Journal of biological chemistry (2012)

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 (SLRP) - in CD14-mediated bacterial phagocytosis. In Psuedomonas aeruginosa lung infections, lumican-deficient (Lum-/-) mice failed to clear the bacterium from the lungs, with a dramatic increase in mortality. In vitro, phagocytosis of non-opsonized gram-negative E .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 (KA= 2.15 x 106 M-1), while rLumY20A, and not rLumY21A, where a tyrosine in each was replaced with an alanine, showed 60 fold decreased binding and failure to restore phagocytosis in Lum-/- MΦs, indicating Y20 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 SLRPs.