title: Enhanced survival of Leishmania major in neutrophil granulocytes in the presence of apoptotic cells.
abstract: Neutrophil granulocytes are the first leukocytes that encounter and phagocytose Leishmania major (L. major) parasites in the infected skin. The parasites can nonetheless survive within neutrophils. However, the mechanisms enabling the survival of Leishmania within neutrophils are still elusive. Previous findings indicated that human neutrophils can engulf apoptotic cells. Since apoptotic neutrophils are abundant in infected tissues, we hypothesized that the uptake of apoptotic cells results in diminished anti-leishmanial activity and, consequently, contributes to enhanced survival of the parasites at the site of infection. In the present study, we demonstrated that L. major-infected primary human neutrophils acquire enhanced capacity to engulf apoptotic cells. This was associated with increased expression of the complement receptors 1 and 3 involved in phagocytosis of apoptotic cells. Next, we showed that ingestion of apoptotic cells affects neutrophil antimicrobial functions. We observed that phagocytosis of apoptotic cells by neutrophils downregulates the phosphorylation of p38 MAPK and PKCδ, the kinases involved in activation of NADPH oxidase and hence reactive oxygen species (ROS) production. In line, uptake of apoptotic cells inhibits TNF- and L. major-induced ROS production by neutrophils. Importantly, we found that the survival of Leishmania in neutrophils is strongly enhanced in neutrophils exposed to apoptotic cells. Together, our findings reveal that apoptotic cells promote L. major survival within neutrophils by downregulating critical antimicrobial functions. This suggests that the induction of enhanced uptake of apoptotic cells represents a novel evasion mechanism of the parasites that facilitates their survival in neutrophil granulocytes.
authors.affiliation: Department of Infectious Diseases and Microbiology, University of Lübeck, Lübeck, Germany.
authors.forename: Natallia
authors.identifier: http://orcid.org/0000-0001-6952-8792
authors.initials: N
authors.lastname: Salei
authors.affiliation: Department of Infectious Diseases and Microbiology, University of Lübeck, Lübeck, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Hellberg
authors.affiliation: Institute for Systemic Inflammation Research, University of Lübeck, Lübeck, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Köhl
authors.affiliation: Department of Infectious Diseases and Microbiology, University of Lübeck, Lübeck, Germany.
authors.forename: Tamás
authors.initials: T
authors.lastname: Laskay
mesh_terms: D000328:Adult; D017209:Apoptosis; D002478:Cells, Cultured; D006801:Humans; D018320:Leishmania major / Q000472:pathogenicity*; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism / Q000382:microbiology*; D010587:Phagocytosis; D051745:Protein Kinase C-delta / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D011951:Receptors, Complement / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D011951:Receptors, Complement; D014409:Tumor Necrosis Factor-alpha; D051745:Protein Kinase C-delta; D048051:p38 Mitogen-Activated Protein Kinases