SOCS-2 desempenha um importante papel regulador em um modelo experimental de infecção pelo Dengue

Abstract

Dengue virus (DV) has emerged as the most relevant arthropod-borne viral disease in tropical areas, reaching millions of cases worldwide each year. During the viral infection, there is a characteristic development of vascular instability, as increased vascular permeability, elevated haemoconcentration and thrombocytopenia are observed. The five-lipoxygenase (5-LO) pathway, is an important axis of balance for the inflammatory processes. The 5-LO pathway is associated with production of both leukotrienes and Lipoxins. Lipoxin is a molecule that have been described with important anti-inflammatory effects and its signaling is associated with SOCS-2 activation. Here, our aim was to evaluate the importance of 5-LO and SOCS-2 in an experimental model of Dengue virus serotype 3 (DEN-3) infection. C57 BL/6 wild type, 5-LO deficient (5-LO-/-) and SOCS-2 deficient (SOCS-2-/-) mice were infected intraperitoneally with 10 PFU of DEN-3. Non-infected mice were used as controls. Our model of DEN-3 infection is followed by great inflammatory response as assessed by cytokine/chemokine production and neutrophil recruitment and severe circulatory dysfunction. On another hand, 5-LO-/- and SOCS-2-/- (but mainly SOCS-2-/-) mice showed an altered inflammatory response, with elevated haemoconcentration and reduced platelet count when compared to the wild type control, indicating a severe response to the infection. They also displayed elevated splenic, hepatic and pulmonary neutrophil influx, and accordingly higher levels of CXCL1 in the liver, spleen, lungs and serum. Furthermore, 5- LO-/- and SOCS-2-/- showed higher levels of splenic and hepatic IL-6 and TNFa, despite lower levels of IFNg in both organs. SOCS-2-/- mice also displayed greatly elevated splenic viral titers. Then, our results suggest that lipoxin may play a protective role in our dengue infection experimental model and that the blockade in both lipoxin production or lipoxin signaling is associated with more severe disease, at least in part, because of the loss of virus load control. On another hand, the role of SOCS-2 as counter-regulator of another SOCS molecules could be of great importance.