title: Bifunctional lipocalin ameliorates murine immune complex-induced acute lung injury.
abstract: Molecules that simultaneously inhibit independent or co-dependent proinflammatory pathways may have advantages over conventional monotherapeutics. OmCI is a bifunctional protein derived from blood-feeding ticks that specifically prevents complement (C)-mediated C5 activation and also sequesters leukotriene B4 (LTB4) within an internal binding pocket. Here, we examined the effect of LTB4 binding on OmCI structure and function and investigated the relative importance of C-mediated C5 activation and LTB4 in a mouse model of immune complex-induced acute lung injury (IC-ALI). We describe two crystal structures of bacterially expressed OmCI: one binding a C16 fatty acid and the other binding LTB4 (C20). We show that the C5 and LTB4 binding activities of the molecule are independent of each other and that OmCI is a potent inhibitor of experimental IC-ALI, equally dependent on both C5 inhibition and LTB4 binding for full activity. The data highlight the importance of LTB4 in IC-ALI and activation of C5 by the complement pathway C5 convertase rather than by non-C proteases. The findings suggest that dual inhibition of C5 and LTB4 may be useful for treatment of human immune complex-dependent diseases.
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, United Kingdom.
authors.forename: Pietro
authors.initials: P
authors.lastname: Roversi
authors.forename: Bernhard
authors.initials: B
authors.lastname: Ryffel
authors.forename: Dieudonnée
authors.initials: D
authors.lastname: Togbe
authors.forename: Isabelle
authors.initials: I
authors.lastname: Maillet
authors.forename: Mauro
authors.initials: M
authors.lastname: Teixeira
authors.forename: Nurfilza
authors.initials: N
authors.lastname: Ahmat
authors.forename: Guido C
authors.initials: GC
authors.lastname: Paesen
authors.forename: Olga
authors.initials: O
authors.lastname: Lissina
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Boland
authors.forename: Kerstin
authors.initials: K
authors.lastname: Ploss
authors.forename: Joseph J E
authors.initials: JJ
authors.lastname: Caesar
authors.forename: Susanne
authors.initials: S
authors.lastname: Leonhartsberger
authors.forename: Susan M
authors.initials: SM
authors.lastname: Lea
authors.forename: Miles A
authors.initials: MA
authors.lastname: Nunn
mesh_terms: D055371:Acute Lung Injury / Q000276:immunology / Q000378:metabolism* / Q000628:therapy; D000818:Animals; D000936:Antigen-Antibody Complex / Q000494:pharmacology*; D060829:Arthropod Proteins / Q000378:metabolism / Q000494:pharmacology*; D002352:Carrier Proteins / Q000378:metabolism / Q000494:pharmacology*; D002849:Chromatography, Gas; D003182:Complement C5 / Q000378:metabolism; D015777:Eicosanoids / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D007124:Immunoenzyme Techniques; D007975:Leukotriene B4 / Q000378:metabolism; D054834:Lipocalins / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011994:Recombinant Proteins / Q000378:metabolism; D012756:Sheep; D020349:Surface Plasmon Resonance; D013917:Thrombin / Q000378:metabolism
chemical_list: D000936:Antigen-Antibody Complex; D060829:Arthropod Proteins; D002352:Carrier Proteins; D003182:Complement C5; D015777:Eicosanoids; D005227:Fatty Acids; D054834:Lipocalins; C521053:OmCI protein, tick; D011994:Recombinant Proteins; D007975:Leukotriene B4; D013917:Thrombin
keywords: Acute Lung Injury; Complement; Immune Complex; Immunotherapy; Inflammation; Leukotriene; Lung Injury; Parasite