Interactions with apoptotic but not with necrotic neutrophils increase parasite burden in human macrophages infected with Leishmania amazonensis

Lilian Afonso^*^,^,1, Valéria M. Borges^*^,^,1, Heloísa Cruz^*^,, Flávia L. Ribeiro-Gomes^,, George A. DosReis^,, Alberto Noronha Dutra^*, Jorge Clarêncio^*, Camila I. de Oliveira^*^,, Aldina Barral^*^,^,, Manoel Barral-Netto^*^,^, and Cláudia I. Brodskyn^*^,^,^,2

^* Centro de Pesquisas Gonçalo Moniz-Fundação Oswaldo Cruz (CPqGM)- Fundação Oswaldo Cruz (FIOCRUZ),
Universidade Federal da Bahia, Salvador, Brazil;
Instituto de Biofísica Carlos Chagas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil; and
Institute of Investigation in Immunology-III, Salvador, Bahia, Brazil

² Correspondence: Laboratório de Imunoparasitologia (LIP), Centro de Pesquisas Gonçalo Moniz (CPqGM/FIOCRUZ), Rua Waldemar Falcão, 121, Candeal, Salvador-BA, 40295-001, Brazil. E-mail: brodskyn{at}bahia.fiocruz.br

ABSTRACT

Neutrophils are involved in the initial steps of most responsesto pathogens. In the present study, we evaluated the effectsof the interaction of apoptotic vs. necrotic human neutrophilson macrophage infection by Leishmania amazonensis. Phagocytosisof apoptotic, but not viable, neutrophils by Leishmania-infectedmacrophages led to an increase in parasite burden via a mechanismdependent on TGF-β1 and PGE₂. Conversely, infected macrophages’uptake of necrotic neutrophils induced killing of L. amazonensis.Leishmanicidal activity was dependent on TNF- ${alpha}$ and neutrophilicelastase. Nitric oxide was not involved in the killing of parasites,but the interaction of necrotic neutrophils with infected macrophagesresulted in high superoxide production, a process reversed bycatalase, an inhibitor of reactive oxygen intermediate production.Initial events after Leishmania infection involve interactionswith neutrophils; we demonstrate that phagocytosis of thesecells in an apoptotic or necrotic stage can influence the outcomeof infection, driving either parasite survival or destruction.

Key Words: apoptosis • necrosis • phagocytosis • TGF-β1 • NE