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

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          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.

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          Most cited references115

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          Crosstalk of reactive oxygen species and NF-κB signaling.

          NF-κB proteins are a family of transcription factors that are of central importance in inflammation and immunity. NF-κB also plays important roles in other processes, including development, cell growth and survival, and proliferation, and is involved in many pathological conditions. Reactive Oxygen Species (ROS) are created by a variety of cellular processes as part of cellular signaling events. While certain NF-κB-regulated genes play a major role in regulating the amount of ROS in the cell, ROS have various inhibitory or stimulatory roles in NF-κB signaling. Here we review the regulation of ROS levels by NF-κB targets and various ways in which ROS have been proposed to impact NF-κB signaling pathways.
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            Estrogen prevents bone loss via estrogen receptor alpha and induction of Fas ligand in osteoclasts.

            Estrogen prevents osteoporotic bone loss by attenuating bone resorption; however, the molecular basis for this is unknown. Here, we report a critical role for the osteoclastic estrogen receptor alpha (ERalpha) in mediating estrogen-dependent bone maintenance in female mice. We selectively ablated ERalpha in differentiated osteoclasts (ERalpha(DeltaOc/DeltaOc)) and found that ERalpha(DeltaOc/DeltaOc) females, but not males, exhibited trabecular bone loss, similar to the osteoporotic bone phenotype in postmenopausal women. Further, we show that estrogen induced apoptosis and upregulation of Fas ligand (FasL) expression in osteoclasts of the trabecular bones of WT but not ERalpha(DeltaOc/DeltaOc) mice. The expression of ERalpha was also required for the induction of apoptosis by tamoxifen and estrogen in cultured osteoclasts. Our results support a model in which estrogen regulates the life span of mature osteoclasts via the induction of the Fas/FasL system, thereby providing an explanation for the osteoprotective function of estrogen as well as SERMs.
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              The Fas death factor

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                Author and article information

                Contributors
                Role: Academic Editor
                Role: Academic Editor
                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                22 February 2021
                February 2021
                : 22
                : 4
                : 2177
                Affiliations
                [1 ]Lung Cellular and Molecular Biology Laboratory, Institute of Pulmonary Medicine, Hadassah Medical Center, The Hebrew University of Jerusalem, Jerusalem 91120, Israel; petukhov@ 123456hadassah.org.il (D.P.); raffibreuer@ 123456gmail.com (R.B.)
                [2 ]Department of Medical Neurobiology, Institute of Medical Research, Hadassah Medical School, The Hebrew University of Jerusalem, Jerusalem 91120, Israel; ronit.ahdut@ 123456mail.huji.ac.il
                [3 ]Department of Science, The David Yellin Academic College of Education, Jerusalem 9103501, Israel
                [4 ]Department of Emergency Medicine, Hadassah Medical School, The Hebrew University of Jerusalem, Jerusalem 91120, Israel; richter@ 123456hadassah.org.il
                Author notes
                [†]

                These authors contributed equally.

                Article
                ijms-22-02177
                10.3390/ijms22042177
                7926921
                33671651
                f541a7d1-c72b-4194-8d82-f60a3bea2020
                © 2021 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 06 December 2020
                : 18 February 2021
                Categories
                Review

                Molecular biology
                soluble fas ligand,aging,autoimmune response,pulmonary disease
                Molecular biology
                soluble fas ligand, aging, autoimmune response, pulmonary disease

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