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The pleiotropic cytokine TNF<jats:italic>\u03b1<\/jats:italic>is one of the major players governing the inflammation in the central nervous system and peripheral districts such as the neuromuscular and immune system. Changes in TNF<jats:italic>\u03b1<\/jats:italic>levels are reported in blood, cerebrospinal fluid, and nerve tissues of ALS patients and animal models. However, whether they play a detrimental or protective role on the disease progression is still not clear. Our group and others have recently reported opposite involvements of TNFR1 and TNFR2 in motor neuron death. TNFR2 mediates TNF<jats:italic>\u03b1<\/jats:italic>toxic effects on these neurons presumably through the activation of MAP kinase-related pathways. On the other hand, TNFR2 regulates the function and proliferation of regulatory T cells (Treg) whose expression is inversely correlated with the disease progression rate in ALS patients. In addition, TNF<jats:italic>\u03b1<\/jats:italic>is considered a procachectic factor with a direct catabolic effect on skeletal muscles, causing wasting. We review and discuss the role of TNF<jats:italic>\u03b1<\/jats:italic>in ALS in the light of its multisystem nature.<\/jats:p>","DOI":"10.1155\/2017\/2985051","type":"journal-article","created":{"date-parts":[[2017,9,10]],"date-time":"2017-09-10T21:00:29Z","timestamp":1505077229000},"page":"1-16","source":"Crossref","is-referenced-by-count":38,"title":["Amyotrophic Lateral Sclerosis, a Multisystem Pathology: Insights into the Role of TNF<i>\u03b1<\/i>"],"prefix":"10.1155","volume":"2017","author":[{"given":"Massimo","family":"Tortarolo","sequence":"first","affiliation":[{"name":"Department of Neuroscience, IRCCS Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniele","family":"Lo Coco","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, IRCCS Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy"},{"name":"ALS Research Center, Dipartimento di Biomedicina Sperimentale e 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