Accuri C6 Flow Cytometer System
Originally published online as doi:10.1189/jlb.1008590 on April 20, 2009

Published online before print April 20, 2009
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(Journal of Leukocyte Biology. 2009;86:81-90.)
© 2009 Society for Leukocyte Biology

A new function of the Fas-FasL pathway in macrophage activation

Reza Chakour*,{dagger},1, Cindy Allenbach*,{dagger},1, Florian Desgranges*,{dagger}, Mélanie Charmoy*,{dagger}, Jacques Mauel{dagger}, Irène Garcia{ddagger}, Pascal Launois*,{dagger}, Jacques Louis*,{dagger},§ and Fabienne Tacchini-Cottier*,{dagger},2

* World Health Organization Immunology Research and Training Centre and
{dagger} Department of Biochemistry, University of Lausanne, Epalinges, Switzerland;
§ Department of Parasitology, Institut Pasteur, Paris, France; and
{ddagger} Department of Pathology, University of Geneva, Switzerland

2. Correspondence: WHO Immunology Research and Training Centre, Department of Biochemistry, University of Lausanne, 155 chemin des Boveresses, CH-1066 Epalinges, Switzerland. E-mail: fabienne.tacchini-cottier{at}unil.ch

ABSTRACT

Upon infection with the protozoan parasite Leishmania major, susceptible BALB/c mice develop unhealing lesions associated with the maturation of CD4+Th2 cells secreting IL-4. In contrast, resistant C57BL/6 mice heal their lesions, because of expansion and secretion of IFN-{gamma} of CD4+ Th1 cells. The Fas-FasL pathway, although not involved in Th cell differentiation, was reported to be necessary for complete resolution of lesions. We investigate here the role of IFN-{gamma} and IL-4 on Fas-FasL nonapoptotic signaling events leading to the modulation of macrophage activation. We show that addition of FasL and IFN-{gamma} to BMMø led to their increased activation, as reflected by enhanced secretion of TNF, IL-6, NO, and the induction of their microbicidal activity, resulting in the killing of intracellular L. major. In contrast, the presence of IL-4 decreased the synergy of IFN-{gamma}/FasL significantly on macrophage activation and the killing of intracellular L. major. These results show that FasL synergizes with IFN-{gamma} to activate macrophages and that the tight regulation by IFN-{gamma} and/or IL-4 of the nonapoptotic signaling events triggered by the Fas-FasL pathway affects significantly the activation of macrophages to a microbicidal state and may thus contribute to the pathogenesis of L. major infection.

Key Words: tumor necrosis factor (TNF) • Leishmania • Toll-like receptors