Novel orally active ligands of lanthionine synthetase C-like protein 2 ameliorate influenza-related inflammation and immunopathology (IRM7P.482)

Abstract

Abstract The use of broad-based drugs that target the host inflammatory response and facilitate recovery has been proposed for treating influenza. We previously identified lanthionine synthetase C-like protein 2 (LANCL2) as a new therapeutic target for inflammatory diseases, predicted in silico that NSC61610 and abscisic acid (ABA) bind to LANCL2 and demonstrated their therapeutic efficacy in mouse models of colitis. Here, we use surface plasmon resonance to demonstrate for the first time that NSC61610 binds to LANCL2, promotes cAMP accumulation and protein kinase A (PKA) phosphorylation in RAW macrophages. To examine the therapeutic efficacy of NSC61610 in vivo, we infected mice with influenza A H1N1pdm virus and determined its impact on influenza-related morbidity, mortality, lung inflammatory profiles and histopathology. Our results demonstrate that oral administration of NSC61610 (20 mg/kg/day) ameliorates influenza by down-modulating pulmonary TNF-α and MCP-1 mRNA expression and reducing the infiltration of neutrophils and pro-inflammatory monocytes in the lungs. The therapeutic actions and signaling of NSC61610 were abrogated following gene silencing by LANCL2 siRNA administration further validating our findings. Thus, binding of NSC61610 to LANCL2 and signaling through cAMP and PKA represents a novel mechanism for modulating pulmonary host responses and improving disease resolution in influenza virus-infected mice.