TY - JOUR
T1 - CLEC5A is critical for dengue virus-induced inflammasome activation in human macrophages
AU - Wu, Ming Fang
AU - Chen, Szu Ting
AU - Yang, An Hang
AU - Lin, Wan Wan
AU - Lin, Yi Ling
AU - Chen, Nien Jung
AU - Tsai, I. Shuen
AU - Li, Lei
AU - Hsieh, Shie Liang
PY - 2013/1/3
Y1 - 2013/1/3
N2 - 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.
AB - 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.
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U2 - 10.1182/blood-2012-05-430090
DO - 10.1182/blood-2012-05-430090
M3 - Article
C2 - 23152543
AN - SCOPUS:84872057098
SN - 0006-4971
VL - 121
SP - 95
EP - 106
JO - Blood
JF - Blood
IS - 1
ER -