title: Neutrophils recruited to the site of Mycobacterium bovis BCG infection undergo apoptosis and modulate lipid body biogenesis and prostaglandin E production by macrophages.
abstract: Neutrophil influx to sites of mycobacterial infections is one of the first events of tuberculosis pathogenesis. However, the role of early neutrophil recruitment in mycobacterial infection is not completely understood. We investigated the rate of neutrophil apoptosis and the role of macrophage uptake of apoptotic neutrophils in a pleural tuberculosis model induced by BCG. Recruited neutrophils were shown to phagocyte BCG and a large number of neutrophils undergo apoptosis within 24 h. Notably, the great majority of apoptotic neutrophils were infected by BCG. Increased lipid body (lipid droplets) formation, accompanied by prostaglandin E(2) (PGE(2)) and TGF-beta1 synthesis, occurred in parallel to macrophage uptake of apoptotic cells. Lipid body and PGE(2) formation was observed after macrophage exposure to apoptotic, but not necrotic or live neutrophils. Blockage of BCG-induced lipid body formation significantly inhibited PGE(2) synthesis. Pre-treatment with the pan-caspase inhibitor zVAD inhibited BCG-induced neutrophil apoptosis and lipid body formation, indicating a role for apoptotic neutrophils in macrophage lipid body biogenesis in infected mice. In conclusion, BCG infection induced activation and apoptosis of infected neutrophils at the inflammatory site. The uptake of apoptotic neutrophils by macrophages leads to TGF-beta1 generation and PGE(2)-derived lipid body formation, and may have modulator roles in mycobacterial pathogenesis.
authors.affiliation: Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil.
authors.forename: Heloisa
authors.initials: H
authors.lastname: D'Avila
authors.forename: Natalia R
authors.initials: NR
authors.lastname: Roque
authors.forename: Rafael M
authors.initials: RM
authors.lastname: Cardoso
authors.forename: Hugo C
authors.initials: HC
authors.lastname: Castro-Faria-Neto
authors.forename: Rossana C N
authors.initials: RC
authors.lastname: Melo
authors.forename: Patrícia T
authors.initials: PT
authors.lastname: Bozza
mesh_terms: D000818:Animals; D017209:Apoptosis; D015232:Dinoprostone / Q000096:biosynthesis*; D005260:Female; D006651:Histocytochemistry; D008055:Lipids / Q000096:biosynthesis*; D008264:Macrophages / Q000276:immunology* / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008853:Microscopy; D046529:Microscopy, Electron, Transmission; D009163:Mycobacterium bovis / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology*; D010994:Pleura / Q000473:pathology; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis; D014396:Tuberculosis, Pleural / Q000276:immunology
chemical_list: D008055:Lipids; D053773:Transforming Growth Factor beta1; D015232:Dinoprostone