FAS Ligand Triggers Pulmonary Silicosis

Abstract

We investigated the role of Fas ligand in murine silicosis. Wild-type mice instilled with silica developed severe pulmonary inflammation, with local production of tumor necrosis factor (TNF)-α, and interstitial neutrophil and macrophage infiltration in the lungs. Strikingly, Fas ligand–deficient generalized lymphoproliferative disease mutant (gld) mice did not develop silicosis. The gld mice had markedly reduced neutrophil extravasation into bronchoalveolar space, and did not show increased TNF-α production, nor pulmonary inflammation. Bone marrow chimeras and local adoptive transfer demonstrated that wild-type, but not Fas ligand–deficient lung macrophages recruit neutrophils and initiate silicosis. Silica induced Fas ligand expression in lung macrophages in vitro and in vivo, and promoted Fas ligand–dependent macrophage apoptosis. Administration of neutralizing anti-Fas ligand antibody in vivo blocked induction of silicosis. Thus, Fas ligand plays a central role in induction of pulmonary silicosis.

Dysregulation of the immune system caused by silica and asbestos

“…Unfortunately, effects of increased FasL expression on macrophage capacity to release proinflammatory appear to be variable; in some cases, the spontaneous release of TNF-α is increased by silica (and the subsequent FasL presence; see Borges et al, 2001) while in other studies, the absence of FasL (i.e. demonstrated using lpr/lpr vs. wild-type mice) results in greater spontaneous release of this and other cytokines (Brown et al, 2004) key to inflammation and anti-tumor activities.…”

“…It is well known that inhaled silica causes increased FasL expression in the lungs (Borges et al, 2001(Borges et al, , 2002Corsini et al, 2003;Zhang et al, 2006). Consequently, an eventual increase in apoptotic death among macrophages in an exposed host's lungs is expected that, with respect to tumor immunity, should then allow any silica-transformed cells that evolve in situ to remain unharmed and able to proliferate.…”

Proinflammatory Clearance of Apoptotic Neutrophils Induces an IL-12lowIL-10high Regulatory Phenotype in Macrophages

“…After 48 h, supernatants were collected and assayed for cytokine and nitrite content. Expression of macrophage differentiation markers LIGHT and SPHK1 was evaluated by cellular ELISA (25) by a modified technique suitable for macrophages, as described previously (26). Briefly, adherent BMDMs (10 4 ) previously cultured in 96-well plates (0.2 ml) were primed overnight with IFN-g and cultured for 3 d with medium, IL-4, or neutrophils (2 3 10 5 ) as above.…”

History, Classification and Pathophysiology of Small Vessel Vasculitis

“…The first step involves an exogenous stimulus that increases neutrophil and macrophage apoptosis. An example is exposure to an inhaled substance like silica, which is known to induce apoptosis in human peripheral blood lymphocytes and to also induce Fas-ligand expression in lung macrophages (in vitro and in vivo), promoting Fasdependent macrophage apoptosis in a murine model of silicosis [96,97]. Similarly, other postulated etiological agents for AASV (propylthiouracil, Streptococcus Pneumoniae) have also been shown to induce/accelerate apoptosis [98,99].…”