Turnover of neutrophils mediated by Fas ligand drives Leishmania major infection.
Apoptosis mediated by Fas ligand (FasL) initiates inflammation characterized by neutrophilic infiltration. Neutrophils undergo apoptosis and are ingested by macrophages. Clearance of dead neutrophils leads to prostaglandin- and transforming growth factor-beta-dependent replication of Leishmania major in macrophages from susceptible mice. How L. major induces neutrophil turnover in a physiological setting is unknown. We show that BALB/c FasL-sufficient mice are more susceptible to L. major infection than are FasL-deficient mice. FasL promotes the apoptosis of infected resident macrophages and attracts neutrophils. Furthermore, FasL-sufficient neutrophils exacerbate L. major replication in macrophages, whereas FasL-deficient neutrophils induce parasite killing. These contrasting effects are due to delaying apoptosis and the clearance of FasL-deficient neutrophils. The transfer of neutrophils exacerbates infection in FasL-sufficient mice but reduces infection in FasL-deficient mice. Depletion of neutrophils abolishes the susceptibility of FasL-sufficient mice. These data illustrate a deleterious role of the FasL-mediated turnover of neutrophils on L. major infection.
Ribeiro-Gomes
Flavia L
FL
Instituto de Biofísica Carlos Chagas Filho, Federal University of Rio de Janeiro, Brazil.
Moniz-de-Souza
Maria Carolina A
MC
Borges
Valeria M
VM
Nunes
Marise P
MP
Mantuano-Barradas
Marcio
M
D'Avila
Heloisa
H
Bozza
Patricia T
PT
Calich
Vera L
VL
DosReis
George A
GA
D000818:Animals; D017209:Apoptosis; D016923:Cell Death / Q000276:immunology; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D053222:Fas Ligand Protein; D018320:Leishmania major / Q000254:growth & development* / Q000276:immunology*; D016773:Leishmaniasis, Cutaneous / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology* / Q000473:pathology*
D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins