Neutrophils are key cells in innate immunity and the first line of host defense. Through countless effector mechanisms as phagocytosis, ROS, NO and NETs release, these cells can kill a range of microbes. In sepsis, neutrophils are the main cells involved in inflammatory response and crucial to patient survival. Recently, new adverse factors have been described as important to sepsis's patient survival, among them, obesity. Innate immune response in obesity has received major attention due to pro-inflammatory cytokine release by macrophages and a large inflammatory infiltrate of macrophages in adipose tissue and liver. It causes a chronic low-grade inflammation associated with obesity leading to low vascular resistance in obese individuals, in response to acute immune response, such as sepsis. Knowing that mTOR pathway is not only related to metabolic pathways because it was already shown that mTOR can be activated via TLRs, previews data from our research group demonstrated the importance of mTOR pathway in innate immune cells. Macrophage polarization to M1 or M2 subtypes is related to mTORC1 and 2 activation. Moreover, mTORC1 inhibition decreased the activation of DCs after LPS stimulus, showing the importance of mTORC1 in these cells. Although studies regarding mTOR pathway in innate immune cells are in progress, a lot is left to be explored, mainly regarding neutrophils. Knowing that and the importance of these cells to host defense, we formulated the hypothesis that mTORC1/2 complexes can modulate neutrophils effector functions, and external factors as obesity could signal via mTOR in neutrophils leading to an impactful crosstalk to disease course. Therefore, the aim of this project is to evaluate the influence of these complexes during immune response against a pathogen in a systemic infection. Moreover, mTOR pathway being associated to metabolism, it is important to understand how metabolic alterations, such as obesity, can modulate the activation of mTOR pathway and the consequences for the neutrophils inflammatory response, mainly. To answer these questions, we are going to use a classic model of systemic inflammation, experimental sepsis, in lean and obese mice, mimetizing distinct metabolic environments. In order to study the involvement of mTOR in neutrophils, we are going to use the cre-lox technology, wherein molecules (Raptor ou Rictorflox/flox) from mTOR pathway are deleted specifically in granulocytic lineage (MRP8cre+). Cellular and molecular biology platforms with biochemistry studies are going to be used to evaluate cellular activation, signaling pathway and their interface to innate immune system and metabolic alteration. Therefore we intend to verify differences in neutrophils, such as phenotypic and functional parameters involving mTOR pathway as well as in the course of the disease.
News published in Agência FAPESP Newsletter about the scholarship: