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Neutrophils contribute to the protection conferred by ArtinM against intracellular pathogens: A study on Leishmania major

Abstract

ArtinM, a D-mannose binding lectin from Artocarpus heterophyllus, hasimmunomodulatory activities through its interaction with N-glycans of immune cells,culminating with the establishment of T helper type 1 (Th1) immunity. This interactionprotects mice against intracellular pathogens, including Leishmania major andLeishmania amazonensis. ArtinM induces neutrophils activation, which is known toaccount for both resistance to pathogens and host tissue injury. Although exacerbatedinflammation was not observed in ArtinM-treated animals, assessment of neutrophilresponses to ArtinM is required to envisage its possible application to design a novelimmunomodulatory agent based on carbohydrate recognition. Herein, we focus on themechanisms through which neutrophils contribute to ArtinM-induced protection againstLeishmania, without exacerbating inflammation. For this purpose, human neutrophilstreated with ArtinM and infected with Leishmania major were analyzed together withuntreated and uninfected controls, based on their ability to eliminate the parasite,release cytokines, degranulate, produce reactive oxygen species (ROS), formneutrophil extracellular traps (NETs) and change life span. We demonstrate thatArtinM-stimulated neutrophils enhanced L. major clearance and at least duplicatedtumor necrosis factor (TNF) and interleukin-1beta (IL-1²) release; otherwise,transforming growth factor-beta (TGF-²) production was reduced by half. Furthermore,ROS production and cell degranulation were augmented. The life span of ArtinMstimulatedneutrophils decreased and they did not form NETs when infected with L.major. We postulate that the enhanced leishmanicidal ability of ArtinM-stimulatedneutrophils is due to augmented release of inflammatory cytokines, ROS production,and cell degranulation, whereas host tissue integrity is favored by their shortened lifespan and the absence of NET formation. Our results reinforce the idea that ArtinM may be considered an appropriate molecular template for the construction of an efficientanti-infective agent. (AU)