Linking neuroinflammation to motor neuron degeneration in ALS: The critical role of CXCL13/CXCR5.

Abstract

Amyotrophic lateral sclerosis (ALS) is characterised by the combined degeneration of spino-bulbar motor neurons and of cortico-spinal neurons, leading to progressive paralysis and death within 3 to 5 years after onset of motor symptoms. Only few therapeutic options besides symptomatic and palliative care treatments exist in ALS, with riluzole still being the reference drug improving survival of a few months. Recently, several interventions such as combination of sodium phenylbutyrate and taurursodiol [[1]Paganoni S Macklin EA Hendrix S Berry JD Elliott MA Maiser S et al.Trial of sodium phenylbutyrate-taurursodiol for amyotrophic lateral sclerosis.N Engl J Med. 2020; 383 (03): 919-930Crossref PubMed Scopus (43) Google Scholar] or high caloric nutritional supplementation [[2]Ludolph AC Dorst J Dreyhaupt J Weishaupt JH Kassubek J Weiland U et al.Effect of high-caloric nutrition on survival in amyotrophic lateral sclerosis.Ann Neurol. 2020; 87: 206-216Crossref PubMed Scopus (43) Google Scholar] showed disease modification activity in at least a subset of patients, although these findings require confirmation in larger studies. Motor neuron degeneration is associated with important neuroinflammation in both mouse models of ALS, and in patients. ALS-related neuroinflammation classically features astrocyte and microglial activation, and other cellular actors of peripheral immunity have been involved. In mouse models, expression of mutant ALS gene in microglia or astrocytes appears critical for disease progression and neuroinflammation [[3]Ban J Sámano C Mladinic M Munitic I Glia in amyotrophic lateral sclerosis and spinal cord injury: common therapeutic targets.Croat Med J. 2019; 60: 109-120Crossref PubMed Scopus (4) Google Scholar], and secreted factors from ALS glial cell types proved toxic to motor neurons [[4]Haidet-Phillips AM Hester ME Miranda CJ Meyer K Braun L Frakes A et al.Astrocytes from familial and sporadic ALS patients are toxic to motor neurons.Nat Biotechnol. 2011; 29: 824-828Crossref PubMed Scopus (518) Google Scholar]. Motor neurons themselves appear to produce neuroinflammatory mediators, either in response to axonal injury or to neuroinflammation [[5]Komine O Yamanaka K Neuroinflammation in motor neuron disease.Nagoya J Med Sci. 2015; 77: 537-549PubMed Google Scholar]. Thus, ALS disease progression leads to the production of a soup of secreted immune mediators that impact, directly or indirectly, on motor neuron degeneration. However, which one(s) of these chemokines and cytokines are instrumental in the progression and could constitute valuable therapeutic target(s) remains poorly characterised. In this article of EBioMedicine, Trolese and colleagues provide evidence for a role of the CXCL13 chemokine in disease progression of ALS [[6]Trolese MC Mariani A Terao M de Paola M Fabbrizio P Sironi F et al.CXCL13/CXCR5 signalling is pivotal to preserve motor neurons in amyotrophic lateral sclerosis.EBioMedicine. 2020; 62103097Summary Full Text Full Text PDF PubMed Scopus (4) Google Scholar]. This study stems from previous results by the same group that identified widely discordant disease progressions in two strains of transgenic mice of different genetic backgrounds expressing mutant SOD1-G93A. Using these two strains, the authors previously identified a prominent upregulation of the chemokine CXCL13 in motor neurons of fast progressing mutant SOD1 mice [[7]Nardo G Iennaco R Fusi N Heath PR Marino M Trolese MC et al.Transcriptomic indices of fast and slow disease progression in two mouse models of amyotrophic lateral sclerosis.Brain. 2013; 136: 3305-3332Crossref PubMed Scopus (45) Google Scholar]. This was a potentially interesting observation as CXCL13 has been found to be upregulated upon axonal injury in spinal dorsal neurons and activate its receptor CXCR5 on astrocytes to modulate the cytokine production and astrocyte activation [[8]Jiang B-C Cao D-L Zhang X Zhang Z-J He L-N Li C-H et al.CXCL13 drives spinal astrocyte activation and neuropathic pain via CXCR5.J Clin Invest. 2016; 126: 745-761Crossref PubMed Scopus (139) Google Scholar]. Furthermore, this CXCL13/CXCR5 pathway has also been highlighted in various neuroinflammatory diseases [[9]Sellebjerg F Börnsen L Khademi M Krakauer M Olsson T Frederiksen JL et al.Increased cerebrospinal fluid concentrations of the chemokine CXCL13 in active MS.Neurology. 2009; 73: 2003-2010Crossref PubMed Scopus (153) Google Scholar,[10]Bagaeva LV Rao P Powers JM Segal BM CXC chemokine ligand 13 plays a role in experimental autoimmune encephalomyelitis.J Immunol. 2006; 176: 7676-7685Crossref PubMed Scopus (82) Google Scholar]. Trolese and collaborators first confirmed the selective overexpression of CXCL13 in motor neurons of fast progressing mice, and showed that its receptor CXCR5 was also upregulated in motor neurons. Importantly, release of CXCL13 in the cerebrospinal fluid (CSF) was progressively increased in ALS mice, suggesting that CXCL13 might act at distant sites throughout disease progression. Surprisingly however, intra-cerebroventricular neutralisation of CXCL13 in fast progressive ALS mice decreased their survival and increased functional impairment. Indeed, knock down of CXCL13 in motor neuron/glial co-cultures exacerbated motor neuron death, while conversely addition of CXCL13 prevented it. These effects might be mediated by astrocytes as CXCL13 inhibition was associated, both in vitro and in vivo, with decreased astrocytosis. CXCL13 and CXCR5 appeared to be also upregulated in motor neurons of ALS patients, but CXCL13 levels were lower in the CSF as compared to non-neurological controls. The present study identifies a critical immune mediator as a possible target for disease modifying therapy in ALS. Altogether, the results of Trolese and collaborators suggest that increased CXCL13/CXCR5 signalling is beneficial in fast progressing mice. Thus, stimulating this pathway might prove useful for patients, although substantial further work is required to ascertain the therapeutic relevance of such strategy. Indeed, while Trolese and collaborators showed that decreasing CXCL13 signaling exacerbates the disease, experiments showing that CXCL13 agonism actually slows down disease progression in mutant SOD1 mice, and possibly also in non-SOD1 based models of ALS, are currently lacking. Another critical step before clinical translation would be to demonstrate that CXCL13 administration or agonism is devoid of adverse effects, especially because CXCL13 has been found to trigger pain hypersensitivity in mouse models [[8]Jiang B-C Cao D-L Zhang X Zhang Z-J He L-N Li C-H et al.CXCL13 drives spinal astrocyte activation and neuropathic pain via CXCR5.J Clin Invest. 2016; 126: 745-761Crossref PubMed Scopus (139) Google Scholar]. Besides identifying a potential therapeutic target, the current study might be a first step towards CXCL13 as a potential biomarker of ALS. In their study, Trolese and collaborators found that CXCL13 levels were decreased in CSF of ALS patients, in particular in spinal onset patients, while increased in patients with multiple sclerosis patients. The potential of CXCL13 as a biomarker in ALS, while possible, still needs to be consolidated in follow up clinical studies, with larger number of patients, and longitudinal follow up in order to study the effects of multiple confounding factors that could not be investigated in these pilot studies and comparison with current prognosis biomarkers such as circulating neurofilament levels. In all, the study by Trolese and colleagues paves the way for further studies not only on CXCL13/CXCR5 pathway but also on other immune mediators that might be involved in disease progression, and provides hope that identification of ALS neuroinflammatory mechanisms might translate in clinically relevant interventions in the near future. Both authors contributed to the final version of the commentary. A.A. reports personal fees from Domain Therapeutics, outside the submitted work. LD reports no conflict of interest. The authors received no financial support for the publication of this article. CXCL13/CXCR5 signalling is pivotal to preserve motor neurons in amyotrophic lateral sclerosisWe hypothesise that MNs activate CXCL13 signalling to attenuate CNS inflammation and prevent the neuromuscular denervation. The low levels of CXCL13 in the CSF of ALS patients might reflect the MN dysfunction, suggesting this chemokine as a potential clinical adjunct to discriminate ALS from other neurological diseases. Full-Text PDF Open Access