Abstract
Abnormal immune responses and cytokine storm are involved in the development of severe dengue, a life-threatening disease with high mortality. Dengue virus-induced neutrophil NETosis response is associated with cytokine storm; while the role of viral factors on the elicitation of excessive inflammation mains unclear. Here we found that treatments of dengue virus envelope protein domain III (EIII), cellular binding moiety of virion, is sufficient to induce neutrophil NETosis processes in vitro and in vivo. Challenges of EIII in inflammasome Nlrp3−/− and Casp1−/− mutant mice resulted in less inflammation and NETosis responses, as compared to the wild type controls. Blockages of EIII-neutrophil interaction using cell-binding competitive inhibitor or selective Nlrp3 inflammasome inhibitors OLT1177 and Z-WHED-FMK can suppress EIII-induced NETosis response. These results collectively suggest that Nlrp3 inflammsome is a molecular target for treating dengue-elicited inflammatory pathogenesis.
Highlights
Dengue is one the most important mosquito borne diseases in the tropical and subtropical areas of the world [1, 2], while specific treatments and effective vaccines are currently unavailable [3,4,5,6,7,8]
Flow cytometry analysis of NETosis markers citrullinated histone H3 (CitH3) [53, 54] and histone H2A family member X (H2AX) [55, 56] revealed that rEIII is sufficient to initiate NETosis in neutrophils; the potency of rEIII is comparable to the classical NETosis inducer phorbol ester [18, 57] (Figure 1A, Supplementary Figure 1, flow cytometry gating; Figure 1B)
We found that, when compared to the neutrophils from wild type mice, Nlrp3 inflammasome-deficient (Nlrp3−/− and Casp1−/−) neutrophils displayed relatively low NETosis levels after treated with rEIII and TPA (Figures 2A–C, cell images; green channels: CitH3, a NETosis marker; Figure 2D, quantified results)
Summary
Dengue is one the most important mosquito borne diseases in the tropical and subtropical areas of the world [1, 2], while specific treatments and effective vaccines are currently unavailable [3,4,5,6,7,8]. Infections with dengue viruses (DENV) can lead to a wide range of clinical manifestations and disease severity. Severe dengue ( known as dengue hemorrhage fever, DHF) is characterized by plasma leakage and abnormal bleeding that can lead to shock and high mortality. Because DHF typically occurs during secondary infections with DENVs, abnormal adaptive immune responses are considered as part of the pathophysiology. Detrimental innate immune responses such as excessive inflammation and cytokine storm are likely the critical pathological changes that lead to exacerbated disease, tissue injuries and ultimate death in DHF [9, 10, 12,13,14,15]
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