Abstract
The C-type lectin member 5A (CLEC5A) is a pattern recognition receptor for members of the Flavivirus family and has critical functions in response to dengue virus and Japanese encephalitis virus. Here we show that CLEC5A is involved in neutrophil extracellular trap formation and the production of reactive oxygen species and proinflammatory cytokines in response to Listeria monocytogenes. Inoculation of Clec5a−/− mice with L. monocytogenes causes rapid bacterial spreading, increased bacterial loads in the blood and liver, and severe liver necrosis. In these mice, IL-1β, IL-17A, and TNF expression is inhibited, CCL2 is induced, and large numbers of CD11b+Ly6ChiCCR2hiCX3CR1low inflammatory monocytes infiltrate the liver. By day 5 of infection, these mice also have fewer IL-17A+ γδ T cells, severe liver necrosis and a higher chance of fatality. Thus, CLEC5A has a pivotal function in the activation of multiple aspects of innate immunity against bacterial invasion.
Highlights
The C-type lectin member 5A (CLEC5A) is a pattern recognition receptor for members of the Flavivirus family and has critical functions in response to dengue virus and Japanese encephalitis virus
Among the proinflammatory cytokines secreted from macrophages after bacterial infection, IL-1β is crucial for induction of a febrile response and differentiation of TH17 and IL-17A-producing γδ T cells[17, 18]
We found that L. monocytogenes induced the phosphorylation of spleen tyrosine kinase (Syk) (Fig. 1a) and p65 (Fig. 1b) in WT macrophages; these responses were significantly impaired in Clec5a−/− and Tlr2−/− macrophages, respectively (Fig. 1a, b)
Summary
The C-type lectin member 5A (CLEC5A) is a pattern recognition receptor for members of the Flavivirus family and has critical functions in response to dengue virus and Japanese encephalitis virus. Blockade of CLEC5A by anti-CLEC5A monoclonal antibody (mAb) attenuates dengue virus-induced and Japanese encephalitis virus-induced lethality, and suppresses dengue virus-mediated activation of the NLRP3 inflammasome and osteolytic activity[4, 8] These findings suggest that CLEC5A has critical functions in flavivirus-induced inflammatory reactions. Via phagocytosis and production of reactive oxygen species (ROS), macrophages, neutrophils and CCR2+ inflammatory monocytes are the first line of host defense against bacterial invasion[9, 10], and depletion of these cells increases susceptibility to systemic Listeriosis[11]. The livers of Clec5a−/− mice develop severe necrosis associated with fewer IL-17A+ γδ T cells and massive infiltration of CCR2+ inflammatory monocytes Together, these data indicate a critical role for CLEC5A in L. monocytogenes-induced innate immunity
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