Dengue virus (DENV) infection causes serious clinical symptoms， including Dengue hemorrhagic fever (DHF) and Dengue shock syndrome (DSS). Vascular permeability change is the main feature of the diseases， and the abnormal expression of pro-inflammation cytokines is the important cause of vascular permeability change. However， the mechanism underlying vascular permeability induced by DENV is not fully elucidated. Here we reveal a distinct mechanism by which DENV infection promotes the NLRP3 inflammasome activation and interleukin-1 beta (IL-1β) release to induce endothelial permeability and vascular leakage in mice. DENV M protein interacts with NLRP3 to facilitate the NLRP3 inflammasome assemble and activation， which lead to the induction of pro-inflammation cytokine IL-1β activation and release. Notably， M can induce vascular leakage in mice tissues through activating NLRP3 inflammasome and IL-1β. More importantly， inflammatory cell infiltration and tissue injuries are induced by M in WT mice tissues， but they are not affected by M in NLRP3 knock-out (NLRP3) mice tissues， and Evans blue intensities in WT mice tissues are significantly higher as compared with NLRP3 mice tissues， demonstrating an essential role of NLRP3 in M-induced vascular leakages in mice. Therefore， we propose that upon DENV infection， M interacts with NLRP3 to facilitate the inflammasome activation and IL-1β secretion， which lead to induction of endothelial permeability and vascular leakage in mice tissues. The important role of the DENV-M-NLRP3-IL-1β axis in the induction of vascular leakage provides new insights into the mechanisms underlying DENV pathogenesis and DENV-associated DHF and DSS development. Dengue virus (DENV) is a mosquito-borne pathogen and its infection is prevalent in over 100 tropical and sub-tropical countries or regions with approximately 2.5 billion people at risk. DENV infection induces a spectrum of clinical symptoms ranging from classical dengue fever (DF) to severe dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). Therefore， it is important to understand the mechanisms underlying DENV pathogenesis. In this study， the authors reveal that the DENV membrane protein (M) interacts with the host NLRP3 protein to promote the NLRP3 inflammasome activation， which leads to the activation and release of pro-inflammation cytokine， interleukin-1 beta (IL-1β). More importantly， the authors demonstrate that M protein can induce vascular permeability and vascular leakage and NLRP3 is required for M-induced vascular leakage in mice tissues. Collectively， this study reveals a distinct mechanism underlying DENV pathogeneses and provides new insights into the development of therapeutic agent for DENV-associated diseases.