Peripheral monocytes are functionally altered and invade the CNS in ALS patients

Abstract

Amyotrophic lateral sclerosis (ALS) is a devastating progressive neurodegenerative disease affecting primarily the upper and lower motor neurons. A common feature of all ALS cases is a well-characterized neuroinflammatory reaction within the central nervous system (CNS). However, much less is known about the role of the peripheral immune system and its interplay with CNS resident immune cells in motor neuron degeneration. Here, we characterized peripheral monocytes in both temporal and spatial dimensions of ALS pathogenesis. We found the circulating monocytes to be deregulated in ALS regarding subtype constitution, function and gene expression. Moreover, we show that CNS infiltration of peripheral monocytes correlates with improved motor neuron survival in a genetic ALS mouse model. Furthermore, application of human immunoglobulins or fusion proteins containing only the human Fc, but not the Fab antibody fragment, increased CNS invasion of peripheral monocytes and delayed the disease onset. Our results underline the importance of peripheral monocytes in ALS pathogenesis and are in agreement with a protective role of monocytes in the early phase of the disease. The possibility to boost this beneficial function of peripheral monocytes by application of human immunoglobulins should be evaluated in clinical trials.

SIRT1 deacetylase in aging‐induced neuromuscular degeneration and amyotrophic lateral sclerosis

“…The major populations increased in ALS and aging were from monocyte and macrophage lineages. These changes are consistent with other studies that have found robust activation of these cells as part of the immune response during ALS disease progression and aging (Butovsky et al, 2012; Chiu et al, 2009; Galbavy et al, 2017; Kullberg, Aldskogius, & Ulfhake, 2001; Zondler et al, 2016). …”

Characterization of Gene Expression Phenotype in Amyotrophic Lateral Sclerosis Monocytes

“…25,26 In mouse models, it has been suggested that peripheral monocytes/macrophages infiltrated spinal cords during the course of disease using Ly6C and CD169 as markers for monocytederived macrophages. 18 Our results indicate that monocytes of patients with ALS may participate in the inflammatory response associated with disease progression; more inflammation-related DEGs are observed in rapid phase than slow phase. Thus, manipulating monocytes at an early stage in disease may directly promote the development of therapy for patients with ALS.…”

“…18,19 All of these data suggest that ALS monocytes are involved in proinflammatory responses and may promote active inflammation. The monocytes isolated by negative selection in our study included both CD16 + and CD16 − monocytes.…”

Comprehensive analysis of the mutation spectrum in 301 German ALS families

“…DNA was extracted from whole EDTA-containing venous blood samples as described 21. Analysis of the C9orf72 repeat length was performed by fragment length analysis and repeat-primed PCR (RP-PCR) using previously published primers 22 23.…”