CLEC5A is critical for dengue virus-induced inflammasome activation in human macrophages.

Persistent high fever is one of the most typical clinical symptoms in dengue virus (DV)-infected patients. However, the source of endogenous pyrogen (eg, IL-1β) and the signaling cascade leading to the activation of inflammasome and caspase-1, which are essential for IL-1β and IL-18 secretion, during dengue infection have not been elucidated yet. Macrophages can be polarized into distinct phenotypes under the influence of GM-CSF or M-CSF, denoted as GM-Mϕ and M-Mϕ, respectively. We found that DV induced high levels of IL-1β and IL-18 from GM-Mϕ (inflammatory macrophage) and caused cell death (pyroptosis), whereas M-Mϕ (resting macrophage) did not produce IL-1β and IL-18 on DV infection even with lipopolysaccharide priming. This observation demonstrates the distinct responses of GM-Mϕ and M-Mϕ to DV infection. Moreover, up-regulation of pro-IL-1β, pro-IL-18, and NLRP3 associated with caspase-1 activation was observed in DV-infected GM-Mϕ, whereas blockade of CLEC5A/MDL-1, a C-type lectin critical for dengue hemorrhagic fever and Japanese encephalitis virus infection, inhibits NLRP3 inflammasome activation and pyrotopsis in GM-Mϕ. Thus, DV can activate NLRP3 inflammasome via CLEC5A, and GM-Mϕ plays a more important role than M-Mϕ in the pathogenesis of DV infection.