Platelets mediate increased endothelium permeability in dengue through NLRP3-inflammasome activation

Abstract

• Dengue infection triggers functional inflammasome assembly in platelets.• Platelets may contribute to increased vascular permeability in dengue virus infection by synthesis and release of IL-1b.Dengue is the most frequent hemorrhagic viral disease and re-emergent infection in the world. Although thrombocytopenia is characteristically observed in mild and severe forms of dengue, the role of platelet activation in dengue pathogenesis has not been fully elucidated. We hypothesize that platelets have major roles in inflammatory amplification and increased vascular permeability during severe forms of dengue. Here we investigate interleukin (IL)-1b synthesis, processing, and secretion in platelets during dengue virus (DV) infection and potential contribution of these events to endothelial permeability during infection. We observed increased expression of IL-1b in platelets and plateletderived microparticles from patients with dengue or after platelet exposure to DV in vitro. We demonstrated that DV infection leads to assembly of nucleotide-binding domain leucine rich repeat containing protein (NLRP3) inflammasomes, activation of caspase-1, and caspase-1-dependent IL-1b secretion. Our findings also indicate that plateletderived IL-1b is chiefly released in microparticles through mechanisms dependent on mitochondrial reactive oxygen speciestriggered NLRP3 inflammasomes. Inflammasome activation and platelet shedding of IL-1b-rich microparticles correlated with signs of increased vascular permeability. Moreover, microparticles from DV-stimulated platelets induced enhanced permeability in vitro in an IL-1-dependent manner. Our findings provide new evidence that platelets contribute to increased vascular permeability in DV infection by inflammasome-dependent release of IL-1b. (Blood. 2013;122(20):3405-3414)

Inflammasomes and its importance in viral infections

“…channel-mediated. IL-1b secretion from platelets plays a crucial role in increased human microvascular endothelial cell permeability in vitro and vascular permeability in clinical cases [65]. Further investigation regarding the mechanism of inflammasome activation by DENV demonstrated that C-type lectin domain family 5 members A (CLEC5A) interacts directly with DENV, triggering NLRP3 inflammasome activation [66].…”

Molecular Regulation of Cell Fate in Cerebral Ischemia: Role of the Inflammasome and Connected Pathways

“…These were expressed in both leukocytes as well as activated endothelium, but also in selected neurons and even in platelets. 44 A large amount of reports define the role of TLRs in ischemic brain injury and neurodegenerative diseases, whereas the consequences of NLR-activation during brain injury are only partially understood up until now.…”

“…23 Local inflammation in atherosclerotic lesions is sustained by cholesterol crystal-induced activation of inflammasomes and platelets could increase the endothelium permeability through NLRP3 inflammasome activation. 44 Inflammasome deficiency reduces the immune barrier in the gut, modifies the microbiom and increases incidence of autoimmune diseases such as autoimmune colitis or hepatitis. NLR, NOD-like receptor.…”

“…97 The significance of pannexin-1 channel-mediated inflammasome activation in neurons and astrocytes-which express a NLPR2 inflammasome-was shown before. 95,98,105 Interestingly, there is also data on NLRP3 inflammasome activation in platelets during viral disease, 44 and platelets stimulated by TLR4 agonists release IL-1β in microparticles. 106 These microparticles have been shown to promote endothelial cell activation and endothelium permeability, thus contributing to the inflammatory response.…”

“…106 These microparticles have been shown to promote endothelial cell activation and endothelium permeability, thus contributing to the inflammatory response. 44,106 Thus, it would be interesting to see if this cellular compartment also substantially contributes to proinflammatory mechanisms in acute stroke patients, possibly in the early phase, as platelets release IL-1β before monocytes. 106 …”