Participação da ubiquitina-ligase SMURF1 na sinalização da resposta inata e na resistência do hospedeiro contra infecções bacterianas

Abstract

ABSTRACT

Inflammation is an essential component of the innate immunity triggered during bacterial infections. Innate immunity cells utilize several Pattern Recognition Receptors (PRR), including Toll-like receptors (TLR), to detect pathogen-associated molecular patterns (PAMP). Once activated by bacterial components, innate immunity cells respond through the secretion of inflammatory cytokines and expression of microbicidal mechanisms important in the initial control of the infection. While proper control of the innate immune response is important in combating bacterial infections, an exacerbated response can lead to tissue damage and a variety of pathological conditions, such as cancer, autoimmune diseases, and septic shock. Previous research has shown that Smurf1, an E3 ubiquitin ligase, plays an important role in regulate the immune response and host resistance against bacterial infections. Furthermore, other studies have shown that Smurf1 directs several important substrates of immune system signaling to proteasomal degradation; however, its role in regulating the immune response against microbial infections is not fully understood. Therefore, this work aims at studying the role of Smurf1 in signaling innate immunity receptors in macrophages and in host resistance against bacterial infections. Our results indicate that Smurf1-/- macrophages showed higher TNF-α and IL-10 production and increased phosphorylation levels of ERK1/2 after LPS treatment. Smurf1-/- animals infected with Salmonella typhimurium showed lower numbers of replicative bacteria in the liver compared to the WT animals and the histopathological analysis of the liver of the animals showed less inflammatory involvement. These results suggest that Smurf1 may act as a negative regulator of ERK1/2 pathway activation in macrophages and plays an important role in regulating innate immunity against Salmonella typhimurium infection. Thus, this study opens new therapeutic prospects for treating infectious and inflammatory diseases.