Distinct regulation of dengue virus-induced inflammasome activation in humanmacrophage subsets

Abstract

Abstract Macrophages (Mϕ) are the major source of inflammatory cytokines and aretarget cells for dengue virus (DV) replication. However, Mϕ areheterogeneous and their phenotypic and functional diversities are influenced bycytokines that regulate their differentiation, tissue distribution, and defenseagainst invading pathogens. In vitro, human primary macrophages arederived from peripheral blood CD14+ monocytes in the presence ofmacrophage colony-stimulating factor (M-CSF) or granulocyte macrophagecolony-stimulating factor (GM-CSF). These are essential for developingtissue/resting macrophages (M-Mϕ) and inflammatory macrophages(GM-Mϕ), respectively. While IFN production is similar between M-Mϕand GM-Mϕ, M-Mϕ cannot produce IL-1β after DV infection. Incontrast, GM-Mϕ is more susceptible to DV infection and DV triggers CLEC5Ain GM-Mϕ to activate NLRP3 inflammasomes, which in turn release IL-18 andIL-1β that are critical for Th17 activation and contribute to diseaseseverity. Thus, GM-Mϕ is more representative than M-Mϕ forinvestigating inflammasome activation in dengue infection, and is invaluable forrevealing the molecular mechanism of pathogen-induced inflammatory reaction.Distinct phenotypes of macrophage subsets under the influence of M-CSF andGM-CSF raise the question of optimal conditions for culturing primarymacrophages to study host-pathogen interaction.