Peripheral Macrophages Influence Disease Progression in Mouse Models of ALS

Post by Shireen Parimoo

What's the science?

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder that affects motor neurons and leads to loss of motor function, muscular atrophy, paralysis, and eventual death. Some cases of familial ALS are linked to the mutant SOD1 gene, which promotes motor neuron death. Motor neurons are surrounded by immune cells known as macrophages (peripheral nervous system) and microglia (central nervous system). Studies show that ALS mice without mutant SOD1 in their microglia live longer, but the precise impact of peripheral macrophages and microglia on motor neuron function and survival in ALS has not yet been identified. This week in Nature Neuroscience, Chiot and colleagues investigated the differential roles of microglia and peripheral macrophages in ALS disease progression.

How did they do it?

The authors used slow-progressing (slow-ALS) and fast-progressing (fast-ALS) mouse models of ALS that over-expressed different variants of the SOD1 gene. They used immunohistochemistry to characterize the morphology, number, location, and immunoreactivity (i.e., immune response) of peripheral macrophages and microglia at different stages of the disease throughout the disease course.

In the fast-ALS mice, the authors performed myeloablative conditioning and a bone marrow transplant to replace mutant peripheral macrophages with (i) control macrophages (without mutant SOD1), or (ii) macrophages with the neurotrophic over-expressing human SOD1 macrophages (non-mutant, wild-type) at the pre-symptomatic and disease onset stages. These macrophages also expressed the green fluorescent protein GFP+ for visualization. Finally, the authors performed an RNA sequencing analysis of microglia and macrophages in the mutant SOD1 and SOD1 wild-type ALS mice to better understand how the genetic profiles of these immune cells were modified in the wild-type mice.

What did they find?

In the fast-ALS mice, there was minimal infiltration of peripheral macrophages into the spinal cord, and only at the late symptomatic stage. In the slow-ALS mice, on the other hand, the number of peripheral macrophages increased at the early symptomatic stage and remained stable throughout, with a small increase at the end-stage of the disease. Nevertheless, the level of infiltrated cells at their peak was only 23% relative to the microglial cell population at the end-stage. This means that the infiltration of peripheral macrophages depends on disease duration but does not represent the major cell population in ALS spinal cords.

The neuroprotective effects of modifying peripheral macrophages depended on the disease stage. Specifically, replacing mutant macrophages with wild-type macrophages at the pre-symptomatic stage decreased immunoreactivity of the macrophages and microglia and delayed symptom onset, but did not increase survival. However, replacing the macrophages at disease onset additionally increased the survival of ALS mice. Macrophages and microglia also showed distinct gene expression profiles throughout the course of the disease in ALS mice. In the wild-type ALS mice that survived longer, there was a downregulation of inflammation-promoting genes in peripheral macrophages and an upregulation of synaptogenesis-promoting genes in microglia. These results highlight how modulating peripheral macrophages in mouse models of ALS can influence spinal cord microglia and impact survival by altering gene expression.

What's the impact?

This is the first study to outline the independent contribution of peripheral macrophages and microglia to disease progression in mouse models of ALS. Additionally, this study demonstrates the beneficial effect of macrophage modification at disease onset on survival. The authors identified the role of inflammatory genes at different stages of ALS progression in central and peripheral immune cells, which has exciting implications for targeted interventions that could slow or potentially halt the course of disease progression.

Chiot et al. Modifying macrophages at the periphery has the capacity to change microglial reactivity and to extend ALS survival. Nature Neuroscience (2020). Access the original scientific publication here.