Protective and Toxic Neuroinflammation in Amyotrophic Lateral Sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a clinically heterogeneous disorder characterized by loss of motor neurons, resulting in paralysis and death. Multiple mechanisms of motor neuron injury have been implicated based upon the more than 20 different genetic causes of familial ALS. These inherited mutations compromise diverse motor neuron pathways leading to cell-autonomous injury. In the ALS transgenic mouse models, however, motor neurons do not die alone. Cell death is noncell-autonomous dependent upon a well orchestrated dialogue between motor neurons and surrounding glia and adaptive immune cells. The pathogenesis of ALS consists of 2 stages: an early neuroprotective stage and a later neurotoxic stage. During early phases of disease progression, the immune system is protective with glia and T cells, especially M2 macrophages/microglia, and T helper 2 cells and regulatory T cells, providing anti-inflammatory factors that sustain motor neuron viability. As the disease progresses and motor neuron injury accelerates, a second rapidly progressing phase develops, characterized by M1 macrophages/microglia, and proinflammatory T cells. In rapidly progressing ALS patients, as in transgenic mice, neuroprotective regulatory T cells are significantly decreased and neurotoxicity predominates. Our own therapeutic efforts are focused on modulating these neuroinflammatory pathways. This review will focus on the cellular players involved in neuroinflammation in ALS and current therapeutic strategies to enhance neuroprotection and suppress neurotoxicity with the goal of arresting the progressive and devastating nature of ALS.

Neuron-Microglia Interactions in Motor Neuron Degeneration. The Inflammatory Hypothesis in Amyotrophic Lateral Sclerosis Revisited

“…Astrocytes also participate in the inflammatory mechanisms associated with motor neuron degeneration [156][157][158] and may play a dual role. Like microglia, astrocytes exert both toxic and protective effects on neurons in a context-dependent manner ( Figure 3).…”

“…Around 30% of ALS patients present decrement on repetitive nerve stimulation [181], and the risk of ALS is increased in people with concomitant myasthenia gravis [182]. This combination of ALS and myasthenia gravis has been reported to occur non-stochastically [183] and, although the reasons for the coincidence are unknown, it may involve a link between the immune system and ALS [156]. Taken together these results suggest that immune processes may drive ALS pathology independently of neural processes, exacerbating motor neuron injury and feeding a cyclic process that sustains neurodegeneration.…”

Neuroimmune and Inflammatory Signals in Complex Disorders of the Central Nervous System

“…It is also possible that chronic neuroinflammation restricted to the CNS can extend to skeletal muscles and then to other organs, becoming a systemic inflammation [135, 136]. Evidence indicates that these cells can exert both neuroprotective and neurotoxic influence on motor pathways [137]. Thus, proinflammatory Ly6C hi CCR2+ monocytes from the blood have been shown to infiltrate mice spinal cord, contributing to the death of the motor neurons.…”

Commentary: Calcium in the pathomechanism of amyotrophic lateral sclerosis - Taking center stage?

“…Nowadays amyotrophic lateral sclerosis is known as a non-cell autonomous 2 , multifactorial 3 and multisystem disease 4 , however its exact origin and all the details of the development of the disorder, relentlessly leading to death, are still unclear. Several pathophysiological processes contributing to the progression of the disease have been disclosed in the last five decades, for instance genetic mutations in more than a dozen of genes 5 , excitotoxicity 6 , oxidative stress 7 , immune/inflammatory processes 8 , mitochondrial dysfunctions 9 and disruption in calcium homeostasis 10 . Significance of calcium ions in different physiological and pathological conditions is a well-known phenomenon, since it has got a prominent biological property in reversible complex formations 11 and second messenger function.…”