Work

Bifunctional Lipocalin Ameliorates Murine Immune Complex-induced Acute Lung Injury

Year: 2013

Type: article

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 (LTB 4 ) within an internal binding pocket. Here, we examined the effect of LTB 4 binding on OmCI structure and function and investigated the relative importance of C-mediated C5 activation and LTB 4 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 LTB 4 (C20). We show that the C5 and LTB 4 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 LTB 4 binding for full activity. The data highlight the importance of LTB 4 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 LTB 4 may be useful for treatment of human immune complex-dependent diseases. Background: OmCI is an ectoparasite-derived anti-inflammatory protein that binds LTB 4 and prevents complement C5 activation. Results: The C5 and LTB 4 binding activities of OmCI are functionally and structurally independent, and OmCI potently inhibits immune complex-induced acute lung injury (IC-ALI). Conclusion: LTB 4 and C5 activation by complement contribute equally to the pathology of IC-ALI. Significance: Dual inhibition of these mediators should be considered for treatment of IC-dependent diseases.

Source: Journal of Biological Chemistry

DOI: 10.1074/jbc.m112.420331