Gliotoxin from Aspergillus fumigatus affects phagocytosis and the organization of the actin cytoskeleton by distinct signalling pathways in human neutrophils.
Gliotoxin is a mycotoxin having a considerable number of immuno-suppressive actions and is produced by several moulds such as Aspergillus fumigatus. In this study, we investigated its toxic effects on human neutrophils at concentrations corresponding to those found in the blood of patients with invasive aspergillosis. Incubation of the cells for 10min with 30-100ng/ml of gliotoxin inhibited phagocytosis of either zymosan or serum-opsonized zymosan without affecting superoxide production or the exocytosis of specific and azurophil granules. Gliotoxin also induced a significant re-organization of the actin cytoskeleton which collapsed around the nucleus leading to cell shrinkage and the disappearance of filopodia. This gliotoxin-induced actin phenotype was reversed by the cAMP antagonist Rp-cAMP and mimicked by pCPT-cAMP indicating that it probably resulted from the deregulation of intracellular cAMP homeostasis as previously described for gliotoxin-induced apoptosis. By contrast, gliotoxin-induced inhibition of phagocytosis was not reversed by Rp-cAMP but by arachidonic acid, another member of a known signalling pathway affected by the toxin. This suggests that gliotoxin can affect circulating neutrophils and favour the dissemination of A. fumigatus by inhibiting phagocytosis and the consequent killing of conidia.
Coméra
Christine
C
INRA UR 66 Laboratoire de Pharmacologie et Toxicologie, 180 chemin de Tournefeuille, 31931 Toulouse Cedex 9, France. christine.comera@toulouse.inserm.fr
André
Karine
K
Laffitte
Joëlle
J
Collet
Xavier
X
Galtier
Pierre
P
Maridonneau-Parini
Isabelle
I
D000199:Actins / Q000378:metabolism* / Q000502:physiology; D016718:Arachidonic Acid / Q000378:metabolism; D001228:Aspergillosis / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D001232:Aspergillus fumigatus / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism; D003599:Cytoskeleton / Q000187:drug effects* / Q000378:metabolism; D005912:Gliotoxin / Q000276:immunology / Q000302:isolation & purification / Q000378:metabolism / Q000633:toxicity*; D006801:Humans; D019255:NADPH Oxidases / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D010587:Phagocytosis / Q000187:drug effects* / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects
D000199:Actins; D016718:Arachidonic Acid; D005912:Gliotoxin; D000242:Cyclic AMP; D019255:NADPH Oxidases