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Hydroxychloroquine Inhibits the Trained Innate Immune Response to Interferons #MMPMID33377122
Rother N; Yanginlar C; Lindeboom RGH; Bekkering S; van Leent MMT; Buijsers B; Jonkman I; de Graaf M; Baltissen M; Lamers LA; Riksen NP; Fayad ZA; Mulder WJM; Hilbrands LB; Joosten LAB; Netea MG; Vermeulen M; van der Vlag J; Duivenvoorden R
Cell Rep Med 2020[Dec]; 1 (9): 100146 PMID33377122show ga
Hydroxychloroquine is being investigated for a potential prophylactic effect in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, but its mechanism of action is poorly understood. Circulating leukocytes from the blood of coronavirus disease 2019 (COVID-19) patients show increased responses to Toll-like receptor ligands, suggestive of trained immunity. By analyzing interferon responses of peripheral blood mononuclear cells from healthy donors conditioned with heat-killed Candida, trained innate immunity can be modeled in vitro. In this model, hydroxychloroquine inhibits the responsiveness of these innate immune cells to virus-like stimuli and interferons. This is associated with a suppression of histone 3 lysine 27 acetylation and histone 3 lysine 4 trimethylation of inflammation-related genes, changes in the cellular lipidome, and decreased expression of interferon-stimulated genes. Our findings indicate that hydroxychloroquine inhibits trained immunity in vitro, which may not be beneficial for the antiviral innate immune response to SARS-CoV-2 infection in patients.