Amyotrophic Lateral Sclerosis, a Multisystem Pathology: Insights into the Role of TNFα

Abstract

Amyotrophic lateral sclerosis (ALS) is considered a multifactorial, multisystem disease in which inflammation and the immune system play important roles in development and progression. The pleiotropic cytokine TNFα 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 TNFα 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 TNFα 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, TNFα is considered a procachectic factor with a direct catabolic effect on skeletal muscles, causing wasting. We review and discuss the role of TNFα in ALS in the light of its multisystem nature.

Inflammatory profiles relate to survival in subtypes of amyotrophic lateral sclerosis

“…Clinical and immunopathologic observations from human and experimental studies support that TNFα, TRAIL, and their respective receptors are involved in the pathogenesis of ALS and are directly implicated in the motor neuron death via the receptor-mediated induction of apoptosis. 6,36,37 However, in previous clinical studies, TNF-α did not correlate with disease duration. 38 We also observed higher levels of TNF-α in the end-stage disease of MND, including patients with ALS, paralleled with reduced TRAIL, suggesting that these have a prominent role as prognostic markers.…”

“…4 Furthermore, elevated levels of IL-6 and IL-1b were observed in CSF and spinal cord tissue from patients with ALS, and activation of the TNF alpha (TNF-α) has been reported in ALS. 5,6 However, these previous studies were based on small heterogeneous patient groups not genotyped for ALSrelated mutations, which may differentially affect the immune system. The aim of the present study is to analyze a panel of cytokines in patients with different clinical and genetic types of motor neuron disease (MND), including ALS, to gain insights into the role(s) of inflammatory cytokines across subtypes of ALS and to investigate the prognostic potential of these biomarkers.…”

Neurodegenerative Susceptibility During Maternal Nutritional Programing: Are Central and Peripheral Innate Immune Training Relevant?

“…Similar to Alzheimer, Parkinson and Huntington, modulation of inflammatory cytokine-dependent pathways prevent neuronal death in ALS models. As we commented previously, the contribution of TNFα or IL-6 ( Figure 1) as etiological causes of ALS pathophysiology remains controversial because of their physiological functions or dual role on the central and peripheral immune activation or as a neurotrophic factors (Tortarolo et al, 2017).…”

“…Also, ALS patients and mouse models of the disease have elevated levels of TNFα, IL-6, and IL-1β in blood and cerebrospinal fluid. In addition to TNF-α upregulation in ALS, TNFR1, and TNFR2 transcripts have also been found to be overexpressed in ALS patients compared with non-neurological controls (Han et al, 2015;Tortarolo et al, 2017). Similar to Alzheimer, Parkinson and Huntington, modulation of inflammatory cytokine-dependent pathways prevent neuronal death in ALS models.…”

Soluble iron accumulation induces microglial glutamate release in the spinal cord of sporadic amyotrophic lateral sclerosis

“…TACE is an iron-activated constitutive cytosolic enzyme that cleaves "inactive" pro-TNFα to form "active" TNFα, which is finally released to the extracellular space. [31][32][33] In relation to this, emerging evidence suggests that TNFα levels are increased in blood, CSF, and CNS of SALS patients, 11,34 and that there is a link between TNFα-related neuroinflammation and glutamatemediated excitotoxicity. 35 GLS-C is a TNFα-upregulated inducible cytosolic enzyme which deaminizes glutamine to form glutamate, which is in turn released to the extracellular space.…”