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.

Fig. 1

Mechanisms of motor neuron injury. Motor neuron injury occurs in amyotrophic lateral sclerosis through both cell autonomous- and noncell-autonomous pathways. Multiple mechanisms can lead to motor neuron injury, which funnel into a final pathway or noncell-autonomous toxicity and neuroinflammation leading to motor neuron death

Fig. 2

Neuroprotective phase of neuroinflammation. Initially in the disease course of amyotrophic lateral sclerosis, there is an early anti-inflammatory or neuroprotective compensatory response of surrounding glia and immune cells. This early response is governed by T helper 2 cells (Th2)/regulatory T lymphocytes (Tregs), M2, and supportive astrocytes secreting neurotrophic factors and decreasing neuronal stress. GLT-1 = glutamate transporter; NTFs = neurotrophic factors

Fig. 3

Cytotoxic phase of neuroinflammation. Late in the course of the disease as the motor neuron becomes damaged, there is a transition from a neuroprotective response to an injurious response by the surrounding glia and immune cells. This is presumed to be a vicious cycle that starts when motor neuron death occurs inciting further inflammation and release of toxic factors