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-1 beta) and the signaling cascade leading to the activation of inflammasome and caspase-1, which are essential for IL-1 beta 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-M phi and M-M phi, respectively. We found that DV induced high levels of IL-1 beta and IL-18 from GM-M phi (inflammatory macrophage) and caused cell death (pyroptosis), whereas M-M phi (resting macrophage) did not produce IL-1 beta and IL-18 on DV infection even with lipopolysaccharide priming. This observation demonstrates the distinct responses of GM-M phi and M-M phi to DV infection. Moreover, up-regulation of pro-IL-1 beta, pro-IL-18, and NLRP3 associated with caspase-1 activation was observed in DV-infected GM-M phi, 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-M phi. Thus, DV can activate NLRP3 inflammasome via CLEC5A, and GM-M phi plays a more important role than M-M phi in the pathogenesis of DV infection. (Blood. 2013; 121(1): 95-106)