Inhibition of the lysine demethylase LSD1 modulates the balance between inflammatory and antiviral responses against coronaviruses

• DOI: 10.1126/scisignal.ade0326
• Publication Date: 2023-12-19T18:58:10Z
• Authors: Luca Mazzarella; Fabio Santoro; Roberto Ravasio; Valeria Fumagalli; Paul E. Massa; Simona Rodighiero; Elena Gavilán; Mauro Romanenghi; Bruno A. Duso; Emanuele Bonetti; Lara Manganaro; Rani Pallavi; Deborah Trastulli; Isabella Pallavicini; Claudia Gentile; Silvia Monzani; Tommaso Leonardi; Sebastiano Pasqua...; Gabriele Buttinelli; Angela Di Martino; Giorgio Fedele; Ilaria Schiavoni; Paola Stefanelli; Giuseppe Meroni; Raffaele de Franc...; Christian Steinku...; Gianluca Fossati; Matteo Iannacone; Saverio Minucci; Pier Giuseppe Pel...
• Keywords: Proinflammatory cytokine; Coronavirus

Innate immune responses to coronavirus infections are highly cell specific. Tissue-resident macrophages, which infected by severe acute respiratory syndrome 2 (SARS-CoV-2) in patients but inconsistently vitro, exert critical conflicting effects secreting both antiviral type I interferons (IFNs) and tissue-damaging inflammatory cytokines. Steroids, the only class of host-targeting drugs approved for treatment disease 2019 (COVID-19), indiscriminately suppress responses, possibly impairing viral clearance. Here, we established vitro culture systems that enabled us separately investigate cell-intrinsic cell-extrinsic proinflammatory activities mouse macrophages with prototypical murine MHV-A59. We showed nuclear factor κB–dependent response infection was selectively inhibited loss lysine demethylase LSD1, previously implicated innate cancer, negligible on IFN response. LSD1 ablation also enhanced an IFN-independent response, blocking egress through lysosomal pathway. The macrophage-intrinsic anti-inflammatory activity Lsd1 inhibition confirmed a humanized model SARS-CoV-2 infection. These results suggest controls against coronaviruses at multiple levels provide mechanistic rationale potentially repurposing inhibitors COVID-19 treatment.