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

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.

Splenectomy Promotes Indirect Elimination of Intraocular Tumors by CD8+ T Cells That Is Associated with IFNγ- and Fas/FasL-Dependent Activation of Intratumoral Macrophages

“…Therefore, Fas expression by CD8 + T cells could engage FasL on tumor-associated Mϕs to induce their activation. Although Fas/FasL interactions have traditionally been considered pro-apoptotic, accumulating evidence indicates that Fas/FasL interactions induce Mϕ activation (31, 32) (33, 34) without apoptosis induction which supports this model.…”

“…Interestingly, FasL expression by CD8 + T cells was not necessary for regression of Luc-E.G7 intraocular tumors. However, Mϕs (31, 32) and CD8 + T cells express both Fas and FasL. Therefore, Fas expression by CD8 + T cells could engage FasL on tumor-associated Mϕs to induce their activation.…”

Immune Consequences of Decreasing Tumor Vasculature with Antiangiogenic Tyrosine Kinase Inhibitors in Combination with Therapeutic Vaccines

“…In support of this hypothesis, we report here that MDSCs and TAMs in both the MC38-CEA and 4T1 tumor models showed a striking increase in the surface expression of 4 activation markers: FAS-L, CXCL-9, CD31, and CD105. These markers have been reported to be upregulated during myeloid-cell activation (38, 39), maturation (40), and a type 2 to type 1 immune activation switch (6). It is possible that, in the presence of normal tumor oxygenation, these myeloid cells could become activated and, perhaps, more tumor-lytic and less immunosuppressive.…”

Role of Toll-Like Receptor 9 Signaling in Experimental Leishmania braziliensis Infection

“…The coverslips were subjected to Diff-Quik staining (Medion Diagnostics, Dudingen, Switzerland) according to the manufacturer's instructions. Supernatant nitrite levels were measured by the Griess reaction as previously described (44). The percentage of infected macrophages and number of intracellular parasites per 100 infected macrophages were determined by 2 different individuals counting 100 macrophages in triplicate coverslips by microscopy.…”