Cytotoxicity of liposome-encapsulated polyinosinic-polycytidylic acid in primary human macrophages is only partially related to interferon-ß

Abstract

Background: We demonstrated (ERJ 2017;50 Suppl. 61:PA2030) that polyinosinic-polycytidylic acid (poly(I:C)) encapsulated within novel cationic pH-sensitive liposomes stimulates a potent interferon (IFN)-β response in primary human monocyte-derived macrophages (MDM). IFN-β response, useful for antiviral defence, often raises concerns of cytotoxicity. Aim: To examine potential cytotoxicity of liposome-encapsulated poly(I:C) in MDM. Methods: MDM were stimulated with liposome-encapsulated poly(I:C) (24 hrs, 1 µg/ml). Outcomes were IFN-β secretion (ELISA), expression of IFN-stimulated CXCL11, IDO1, RSAD2 mRNAs (qPCR), secretion of IFN-stimulated cytokine CXCL10 (ELISA), and cytotoxicity (MTT assay). Before stimulation, some MDM were treated with an anti-IFN-β antibody to block secreted IFN-β. As a positive control, MDM were treated with exogenous IFN-β (24 hrs, 10 ng/ml). Results: MDM stimulated with liposome-encapsulated poly(I:C) secreted up to 1 ng/ml of IFN-β. This IFN-β response was paralleled by approx. 50% cytotoxicity. In contrast, when MDM were treated with 10 ng/ml of exogenous IFN-β, no cytotoxicity was observed. The IFN-β antibody efficiently blunted upregulation of IFN-stimulated genes and secretion of CXCL10 in stimulated MDM. Yet the antibody incompletely reversed the cytotoxicity caused by liposome-encapsulated poly(I:C). Conclusion: Cytotoxicity of liposome-encapsulated poly(I:C) is only partially related to IFN-β response. Identification of synergistic cytotoxic mechanisms of liposome-encapsulated poly(I:C) will yield potent and safe antiviral. Funding: Krieble Foundation; Gosselin Foundation; NSERC. ND and AD: co-first authors.