Chiot A, Zaïdi S, Iltis C, Ribon M, Berriat F, Schiaffino L, Jolly A, de la Grange P, Mallat M, Bohl D, Millecamps S, Seilhean D, Lobsiger CS, Boillée S. Modifying macrophages at the periphery has the capacity to change microglial reactivity and to extend ALS survival. Nat Neurosci. 2020 Nov;23(11):1339-1351. Epub 2020 Oct 19 PubMed.
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Houston Methodist
These findings raise many questions. Are the peripheral macrophages affected prior to the CNS microglia being harmed? Is it a direct effect on the macrophages or are the macrophages indirectly affected by other cells, such as altered T regulatory cells or dendritic cells? The macrophages are certainly involved in the disease process, but they may not be the sole culprits and might be dictated to by something upstream. Upstream cells could be a variety of other immune cells that may be somewhat dysfunctional, and therefore, the macrophages can cause further difficulty. As for their effects on microglia, the macrophages might be talking with the neurons, rather than directly with the microglia. This is a neuronal-myeloid interaction, where both the macrophages and microglia influence neurons and other immune cells as well.
The results of this study are not surprising, but rather confirming. The predominant notion in ALS research is that ALS may start as an axonopathy where the axon dies back from the neuromuscular junction. However, a large group of researchers believes that it is not a bottom-up difficulty, it is a top-down one that starts from the cortex of the brain. This study is confirming because it suggests that axonopathy and neuromuscular junction impairment may be very early events whereby macrophages may be signaled to become “bad guys.” Replacing them with “good” macrophages can offer a layer of protection for the axons.
References:
Kano O, Beers DR, Henkel JS, Appel SH. Peripheral nerve inflammation in ALS mice: cause or consequence. Neurology. 2012 Mar 13;78(11):833-5. PubMed.
View all comments by Stanley AppelSant Pau Biomedical Research Institute
In this study, Chiot and colleagues investigate the role of peripheral macrophages, located along peripheral motor neuron axons, and microglia, which surround the spinal motor neuron soma, in ALS. The authors use busulfan and transplantation of GFP+ bone marrow cells to replace peripheral macrophages with macrophages expressing less neurotoxic reactive oxygen species in SOD1 mouse models. Interestingly, their results elegantly show that this modulation, if performed at disease onset, reduces the activation of peripheral macrophages, but also of microglial cells, and extends survival.
One of the most interesting findings indicates that modifying the peripheral compartment may have an impact on the CNS and highlights the importance of studying peripheral immune cells.
Using unbiased technologies, such as single-cell RNA sequencing, to disentangle the heterogeneity of immune cells in the periphery and their gene expression profiles will certainly boost our understanding of the complex crosstalk between the peripheral and the central immune system. In this regard, it will be interesting to unravel how peripheral macrophages modulate microglial cells in the CNS, and if other cell types participate in this communication. A recent study suggested a role of natural killer cells on disease onset and progression in ALS and in the modulation of the microglial phenotype (Garofalo et al., 2020).
Finally, modulation of peripheral macrophages represents a new therapeutic strategy which might have implications in other neurodegenerative diseases. Importantly, these beneficial effects only occur when transplantation is performed at disease onset, which underscores the need of accurate biomarkers to diagnose ALS and enroll patients in clinical trials at early disease stages.
References:
Garofalo S, Cocozza G, Porzia A, Inghilleri M, Raspa M, Scavizzi F, Aronica E, Bernardini G, Peng L, Ransohoff RM, Santoni A, Limatola C. Natural killer cells modulate motor neuron-immune cell cross talk in models of Amyotrophic Lateral Sclerosis. Nat Commun. 2020 Apr 14;11(1):1773. PubMed.
View all comments by Oriol Dols-IcardoUniversity of Edinburgh and UK DRI
Like Séverine Boillée’s landmark observations in 2003, this elegant study once more highlights the therapeutic potential of myeloid cells in motor neuron disease.
It would be fascinating to find out how and which bone marrow- and yolk-sac-derived macrophages in peripheral nerves communicate with CNS microglia. Single-cell transcriptomic analysis and fate mapping may help to resolve this.
It appears from this study that the conditioning regimen for bone marrow transplantation plays a crucial role in attenuating the disease course in SOD1 mutant mice as the transplantation of wild-type bone marrow cells into irradiated mice conferred protection in previous studies, which was not the case with this busulfan protocol. The reduction in circulating white blood cells was also lower in irradiated than in busulfan-treated mice prior to transplantation, and important qualitative differences in compartmental myeloid cell reconstitution may exist.
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