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Bifunctional lipocalin inhibitor of C5 and leukotriene B4 is protective in experimental immune complex alveolitis

Nunn, Miles A.; Roversi, Pietro; Maillet, Isabelle; Ahmat, Nurfilza; Togbe, Dieudonee; Quesniaux, V. F.J.; Teixeira, Mauro; Lissina, Olga; Boland, Wilhelm; Ploss, Kerstin; Leonhartsberger, Susanne; Ryffel, Bernhard; Lea, Susan M.. 2010 Bifunctional lipocalin inhibitor of C5 and leukotriene B4 is protective in experimental immune complex alveolitis. Molecular Immunology, 47. 2279. 10.1016/j.molimm.2010.05.242

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Abstract/Summary

OmCI is an ectoparasite derived bifunctional lipocalin that inhibits complement (C) by binding to C5 and also captures the proinflammatory eicosanoid leukotriene B4 (LTB4). We present the crystal structure of recombinant bacterial bOmCI with and without LTB4 at 2.1 Å resolution, and test the relative contributions of C5 inhibition and LTB4 binding to amelioration of experimental immune complex acute lung injury alveolitis (IC-ALI). The structure shows why OmCI is able to accommodate LTB4, arachidonic acid (AA) and 12-OH hydroxyeicosatetraenoic acid (HETEs), but not cysteinyl leukotrienes, prostaglandins or thromboxanes. It also reveals that only minor structural changes occur when bOmCI is bound to LTB4 rather than palmitoleic acid (C16H30O2) which is the dominant fatty acid in the binding pocket of recombinant bOmCI. In accord with the minor structural changes and use of opposite faces of OmCI for C5 binding and entry of LTB4, the two activities of the protein appear to be entirely independent - since the binding kinetics to LTB4 do not change when bOmCI is bound to C5 and the affinity for C5 and inhibition of C activation is unaltered by binding LTB4. In a mouse model of IC-ALI OmCI inhibited neutrophil recruitment and microvascular damage, and reduced protein exudation in the bronchoalveolar space. To examine the relative importance of OmCIs independent inhibitory activities in IC-ALI, OmCI was saturated with LTB4. The saturated protein was a less potent inhibitor of lung inflammation, though both LTB4 binding and C inhibition were required for maximum effect. The dual activity of OmCI may have advantages over conventional biotherapeutics, such as monoclonal antibodies, which typically target only single components of the immune system

Item Type: Publication - Article
Digital Object Identifier (DOI): 10.1016/j.molimm.2010.05.242
Programmes: CEH Topics & Objectives 2009 - 2012 > Biodiversity > BD Topic 1 - Observations, Patterns, and Predictions for Biodiversity
CEH Sections: Hails
ISSN: 0161-5890
Additional Information. Not used in RCUK Gateway to Research.: The abstract is the whole article and it can be accessed via the OFFICIAL URL link
NORA Subject Terms: Biology and Microbiology
Date made live: 28 Sep 2010 11:57
URI: http://nora.nerc.ac.uk/id/eprint/11042

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