Uptake of apoptotic cells drives the growth of a pathogenic trypanosome in macrophages.
After apoptosis, phagocytes prevent inflammation and tissue damage by the uptake and removal of dead cells. In addition, apoptotic cells evoke an anti-inflammatory response through macrophages. We have previously shown that there is intense lymphocyte apoptosis in an experimental model of Chagas' disease, a debilitating cardiac illness caused by the protozoan Trypanosoma cruzi. Here we show that the interaction of apoptotic, but not necrotic T lymphocytes with macrophages infected with T. cruzi fuels parasite growth in a manner dependent on prostaglandins, transforming growth factor-beta (TGF-beta) and polyamine biosynthesis. We show that the vitronectin receptor is critical, in both apoptotic-cell cytoadherence and the induction of prostaglandin E2/TGF-beta release and ornithine decarboxylase activity in macrophages. A single injection of apoptotic cells in infected mice increases parasitaemia, whereas treatment with cyclooxygenase inhibitors almost completely ablates it in vivo. These results suggest that continual lymphocyte apoptosis and phagocytosis of apoptotic cells by macrophages have a role in parasite persistence in the host, and that cyclooxygenase inhibitors have potential therapeutic application in the control of parasite replication and spread in Chagas' disease.
Freire-de-Lima
C G
CG
Instituto de Biofisica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, RJ, Brazil. gdosreis@biof.ufrj.br
Nascimento
D O
DO
Soares
M B
MB
Bozza
P T
PT
Castro-Faria-Neto
H C
HC
de Mello
F G
FG
DosReis
G A
GA
Lopes
M F
MF
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D014355:Chagas Disease / Q000276:immunology / Q000469:parasitology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000096:biosynthesis / Q000502:physiology; D008264:Macrophages / Q000469:parasitology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009336:Necrosis; D010587:Phagocytosis / Q000502:physiology; D011700:Putrescine / Q000096:biosynthesis / Q000502:physiology; D019030:Receptors, Vitronectin / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000502:physiology; D014349:Trypanosoma cruzi / Q000254:growth & development*
D000590:Amino Acid Chloromethyl Ketones; D015853:Cysteine Proteinase Inhibitors; D019030:Receptors, Vitronectin; D016212:Transforming Growth Factor beta; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D015232:Dinoprostone; D011700:Putrescine