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: Pietro Roversi, Bernhard Ryffel, Dieudonnée Togbe, Isabelle Maillet, Mauro Teixeira, Nurfilza Ahmat, Guido C Paesen, Olga Lissina, Wilhelm Boland, Kerstin Ploss, Joseph J E Caesar, Susanne Leonhartsberger, Susan M Lea, Miles A Nunn
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 288 Issue 26 Pg. 18789-802 (Jun 28 2013) ISSN: 1083-351X [Electronic] United States
• PMID: 23625922 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigen-Antibody Complex
• Arthropod Proteins
• Carrier Proteins
• Complement C5
• Eicosanoids
• Fatty Acids
• Lipocalins
• OmCI protein, tick
• Recombinant Proteins
• Leukotriene B4
• Thrombin

Topics

• Acute Lung Injury (immunology, metabolism, therapy)
• Animals
• Antigen-Antibody Complex (pharmacology)
• Arthropod Proteins (metabolism, pharmacology)
• Carrier Proteins (metabolism, pharmacology)
• Chromatography, Gas
• Complement C5 (metabolism)
• Eicosanoids (metabolism)
• Fatty Acids (metabolism)
• Immunoenzyme Techniques
• Leukotriene B4 (metabolism)
• Lipocalins (metabolism, pharmacology)
• Male
• Mice
• Mice, Inbred C57BL
• Recombinant Proteins (metabolism)
• Sheep
• Surface Plasmon Resonance
• Thrombin (metabolism)