Dengue virus-activated platelets modulate monocyte immunometabolic response through lipid droplet biogenesis and cytokine signaling

Abstract

Dengue is characterized as one of the most important arthropod-borne human viral diseases, representing a public health problem. Increased activation of immune cells is involved in the progression of infection to severe forms. Recently, our group demonstrated the contribution of platelet-monocyte interaction to inflammatory responses in dengue, adding to evolving evidence that platelets have inflammatory functions and can regulate different aspects of innate immune responses. Furthermore, stimuli-specific-activated platelets can promote phenotypic changes and metabolic reprogramming in monocytes. Thus, this study aimed to evaluate the roles of dengue virus (DENV)-activated platelets on immunometabolic reprogramming of monocytes in vitro, focusing on lipid droplet (LD) biogenesis. We demonstrated that platelets exposed to DENV in vitro form aggregates with monocytes and signal to LD formation and CXCL8/IL-8, IL-10, CCL2, and PGE 2 secretion. Pharmacologic inhibition of LD biogenesis prevents PGE 2 secretion, but not CXCL8/IL-8 release, by platelet-monocyte complexes. In exploring the mechanisms involved, we demonstrated that LD formation in monocytes exposed to DENV-activated platelets is partially dependent on platelet-produced MIF. Additionally, LD formation is higher in monocytes, which have platelets adhered on their surface, suggesting that beyond paracrine signaling, platelet adhesion is an important event in platelet-mediated modulation of lipid metabolism in monocytes. Together, our results demonstrate that activated platelets aggregate with monocytes during DENV infection and signal to LD biogenesis and the secretion of inflammatory mediators, which may contribute to dengue immunopathogenesis.

Role of Platelet Cytokines in Dengue Virus Infection

“…LD formation is higher in monocytes, which have platelets adhered on their surface, suggesting the importance of adhesion besides paracrine signaling. Activated platelets aggregate with monocytes during DENV infection and lead to LD biogenesis and release of inflammatory mediators (Barbosa-Lima et al, 2020).…”

Innate immune receptors in platelets and platelet-leukocyte interactions

“…[125][126][127][128][129] Besides contact-dependent signaling, platelet soluble factors participate in leukocyte reprogramming during platelet-leukocyte interactions. 122,130,131 The interaction between platelets and neutrophils is well established ( Fig. 2A).…”

“…Integrin αIIbβ3 and Mac‐1 fibrinogen receptors also play important roles in platelet‐leukocyte aggregation, 125–129 hence fibrinogen bridges platelet and leukocyte integrins 125–129 . Besides contact‐dependent signaling, platelet soluble factors participate in leukocyte reprogramming during platelet‐leukocyte interactions 122,130,131 …”

“…Complementary in vitro experiments show that cytokine secretion by platelet‐monocyte interaction is regulated by P‐selectin‐mediated adhesion and phosphatidylserine recognition on activated and apoptotic platelets 138 . In addition, combined signaling of platelet adhesion plus MIF from DENV‐infected platelets induces lipid droplets biogenesis and PGE 2 synthesis in monocytes 131 . During platelet‐neutrophil interactions, platelet MVs from CLEC2 activation act upon neutrophil CLEC5 and TLR2 inducing NET release 75 .…”

“…138 In addition, combined signaling of platelet adhesion plus MIF from DENV-infected platelets induces lipid droplets biogenesis and PGE 2 synthesis in monocytes. 131 During platelet-neutrophil interactions, platelet MVs from CLEC2 activation act upon neutrophil CLEC5 and TLR2 inducing NET release. 75 Platelet-induced CLEC5 and TLR2-dependent NETosis increase endothelial permeability in co-culture with endothelial cells and in experimental DENV infection in mice.…”