Activation and survival of neutrophils induced by ArtinM: signaling pathways and mechanisms that favor protection against intracellular pathogens

Abstract

The study of ArtinM, a lectin obtained from seeds of Artocarpus heterophyllus, is interest due its important immunomodulatory activity, which induces protection against several intracellular pathogens such as Leishmania major, Listeria monocytogenes and Paracoccidioides brasiliensis. This protection is triggered by the recognition of glycans by ArtinM on receptors of immune cells surface such as neutrophils, macrophages and dendritic cells. The interaction with these cells is followed by a significant increase of IL-12, TNF-± and other inflammatory mediators, indicating the development of Th1 immunity, crucial in the control of intracellular pathogens. Neutrophils can be the immune cells that trigger the lectin-induced resistance. In neutrophils the lectin interacts with N-glycans associated with the surface of TLR2 and CXCR2 promoting phosphorylation of intracellular tyrosine kinases, the L-selectin "shedding", the release of inflammatory mediators and increasing the effector functions of these cells, such as phagocytosis and killing of microorganisms.Recently, we obtained results showing that the in vitro treatment with ArtinM substantially inhibits human neutrophil spontaneous apoptosis, promote cell degranulation and persistent expression of surface molecules, which indicate cellular activation. The degranulation is important in the response against intracellular pathogens by to promote the contact of granules products with macrophages and dendritic cells, since it was stimulated, these cells perform an efficient effector response. Also was found out that ArtinM modifies the course of the survival in neutrophils infected with L. major, and this event can facilitate the elimination of the pathogen.The mechanisms whereby ArtinM exerts its effects in neutrophil activation, altering their survival and eliminating pathogens, are still poorly understood. It is necessary to demonstrate unequivocally the intracellular pathways involved in the response of neutrophils to stimulation by the lectin. Some authors postulate that neutrophils, when properly stimulated, influence immunity by adjusting the function of other cells, favoring the response against aggressors. Accordingly, it is essential to understand the mechanisms triggered by stimulation of neutrophils with ArtinM, in order to elucidate the role of these cells in favor of protection against intracellular pathogens. This project was designed to investigate how neutrophils stimulated with ArtinM participate in the profile of protective response against intracellular pathogens.The goals of this proposal are: (1) to analyze the effect of ArtinM on the release of neutrophil products and their functional consequences, (2) to investigate the intracellular pathways involved in the survival and adhesion of neutrophils stimulated by ArtinM, (3) to investigate the consequences of the interaction of neutrophils stimulated by ArtinM with dendritic cells and natural killer cells to set a response effective in eliminating L. major.We believe that this proposal is in harmony with the contemporary knowledge about the biology of neutrophils. According to the current view, not only neutrophils play the role that is usually assigned to them such as professional phagocytes of the innate immunity, but these cells, when properly activated, can cooperate with other immune cells, particularly dendritic cells and natural killer lymphocytes, modulating their functions, resulting an effective effector response, similar to that provided by the in vivo treatment with ArtinM. It is possible that studies using ArtinM in neutrophils activation, contribute to the biology of these cells is better understood.