sFasL—The Key to a Riddle: Immune Responses in Aging Lung and Disease

Abstract

By dint of the aging population and further deepened with the Covid-19 pandemic, lung disease has turned out to be a major cause of worldwide morbidity and mortality. The condition is exacerbated when the immune system further attacks the healthy, rather than the diseased, tissue within the lung. Governed by unremittingly proliferating mesenchymal cells and increased collagen deposition, if inflammation persists, as frequently occurs in aging lungs, the tissue develops tumors and/or turns into scars (fibrosis), with limited regenerative capacity and organ failure. Fas ligand (FasL, a ligand of the Fas cell death receptor) is a key factor in the regulation of these processes. FasL is primarily found in two forms: full length (membrane, or mFasL) and cleaved (soluble, or sFasL). We and others found that T-cells expressing the mFasL retain autoimmune surveillance that controls mesenchymal, as well as tumor cell accumulation following an inflammatory response. However, mesenchymal cells from fibrotic lungs, tumor cells, or cells from immune-privileged sites, resist FasL+ T-cell-induced cell death. The mechanisms involved are a counterattack of immune cells by FasL, by releasing a soluble form of FasL that competes with the membrane version, and inhibits their cell death, promoting cell survival. This review focuses on understanding the previously unrecognized role of FasL, and in particular its soluble form, sFasL, in the serum of aged subjects, and its association with the evolution of lung disease, paving the way to new methods of diagnosis and treatment.

Diagnostic and prognostic significance of cell death markers in patients with cirrhosis and acute decompensation

“…Noteworthy, sFasL competitive binding to Fas receptor produces anti-apoptotic and anti-cell death effects in nuclei of target cells via activation of pro-survival signaling cascades. In the decompensated liver cirrhosis group, this cellular stress response might be attenuated or abolished due to the progressive loss of function of the cells [ 46 – 48 ]. Regarding our observations on the GGT, previous studies already found GGT levels paralleled with elevated serum ferritin levels [ 49 ] to correlate with liver inflammation in patients with cirrhosis [ 50 ].…”

Aging whole blood transcriptome reveals candidate genes for SARS-CoV-2-related vascular and immune alterations

“…Furthermore, considering that age represents a confounding factor in different pathologies, we cannot determine whether the blood changes are caused by the aging process itself, SARS-CoV-2 infection, or a combination of these events. While age-dependent changes in FASLG expression have already been recognized and were also linked to aging lung and respiratory disease, there are conflicting data on its active form, expression, and serum levels regarding inflammation and apoptosis [ 88 ]. Another important aspect to be disclosed is that lymphocytopenia, a common cause associated with COVID-19, could not be evaluated using the whole blood samples available from the GTEx Biobank.…”

Exploring extracellular vesicles as mediators of clinical disease and vehicles for viral therapeutics: Insights from the COVID-19 pandemic

“…Apoptosis and necrosis of epithelial cells during ALI induced by SARS-CoV-2 is another important factor to consider in severe COVID-19. SARS-CoV-2 can induce cell death of lung epithelial cells by activating caspase-8, which can also contribute to immune activation through the induction of caspase-8-dependent expression of proinflammatory cytokines [50][51][52] . In addition, Fas Ligand (FasL) is an activator of caspase-8mediated apoptosis in cells that express the death receptor Fas, the receptor for FasL, and is observed on the surface of EVs in chronic lung disease [53][54][55] .…”

“…SARS-CoV-2 can induce cell death of lung epithelial cells by activating caspase-8, which can also contribute to immune activation through the induction of caspase-8-dependent expression of proinflammatory cytokines [ 50 – 52 ] . In addition, Fas Ligand (FasL) is an activator of caspase-8-mediated apoptosis in cells that express the death receptor Fas, the receptor for FasL, and is observed on the surface of EVs in chronic lung disease [ 53 – 55 ] . Cells expressing the death receptor Fas may include lung epithelial cells, virally infected cells, and T-lymphocytes which are all highly implicated in COVID-19 pathophysiology, especially during ALI/ARDS [ 53 ] .…”

“…In addition, Fas Ligand (FasL) is an activator of caspase-8-mediated apoptosis in cells that express the death receptor Fas, the receptor for FasL, and is observed on the surface of EVs in chronic lung disease [ 53 – 55 ] . Cells expressing the death receptor Fas may include lung epithelial cells, virally infected cells, and T-lymphocytes which are all highly implicated in COVID-19 pathophysiology, especially during ALI/ARDS [ 53 ] . Interestingly, soluble FasL competes with membrane-associated FasL (mFasL) for binding to the death receptor Fas and, as a result, blocks cell death, highlighting that it is specifically mFasL that induces apoptosis [ 53 , 56 ] .…”