Expression profile of pattern recognition receptors in skeletal muscle of SOD1<sup>(G93A)</sup> amyotrophic lateral sclerosis (ALS) mice and sporadic ALS patients

Lehmann, Swen; Esch, Eric van; Hartmann, Philipp; Goswami, Anand; Nikolin, Stefan; Weis, Joachim; Beyer, Cordian; Johann, Sonja

doi:10.1111/nan.12483

Cited by 29 publications

(22 citation statements)

References 127 publications

(156 reference statements)

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“…On the other hand, lower caspase-1 gene expression in spinal cord in non-treated SOD1G93A mice was already described by our group, which is in accordance with our results [16]. NLRP3 inflammasome is also active in the skeletal muscle, showing increased levels of caspase-1 and IL-1β in pre-symptomatic SOD1G93A mice, and in denervated muscles from these mice and ALS patients [39]. According to our results, TTC could have a role in palliating the effects of active caspase-1 in EDL, but not in SOL.…”

Section: Discussionsupporting

confidence: 93%

Neuroprotective Fragment C of Tetanus Toxin Modulates IL-6 in an ALS Mouse Model

Moreno-Martínez

Torre

Muñoz

et al. 2020

Toxins

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Neuroinflammation plays a significant role in amyotrophic lateral sclerosis (ALS) pathology, leading to the development of therapies targeting inflammation in recent years. Our group has studied the tetanus toxin C-terminal fragment (TTC) as a therapeutic molecule, showing neuroprotective properties in the SOD1G93A mouse model. However, it is unknown whether TTC could have some effect on inflammation. The objective of this study was to assess the effect of TTC on the regulation of inflammatory mediators to elucidate its potential role in modulating inflammation occurring in ALS. After TTC treatment in SOD1G93A mice, levels of eotaxin-1, interleukin (IL)-2, IL-6 and macrophage inflammatory protein (MIP)-1 alpha (α) and galectin-1 were analyzed by immunoassays in plasma samples, whilst protein expression of caspase-1, IL-1β, IL-6 and NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) was measured in the spinal cord, extensor digitorum longus (EDL) muscle and soleus (SOL) muscle. The results showed reduced levels of IL-6 in spinal cord, EDL and SOL in treated SOD1G93A mice. In addition, TTC showed a different role in the modulation of NLRP3 and caspase-1 depending on the tissue analyzed. In conclusion, our results suggest that TTC could have a potential anti-inflammatory effect by reducing IL-6 levels in tissues drastically affected by the disease. However, further research is needed to study more in depth the anti-inflammatory effect of TTC in ALS.

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Section: Discussionsupporting

confidence: 93%

Neuroprotective Fragment C of Tetanus Toxin Modulates IL-6 in an ALS Mouse Model

Moreno-Martínez

Torre

Muñoz

et al. 2020

Toxins

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“…In our view, this discrepancy between ALS and our CTB-Sap model confirms that ALS is not a cell-autonomous MN disease and that different cell types, including muscle fibers, are independently involved in the pathological processes [29,30,31], whereas the muscle modifications observed in the CTB-Sap model are produced by denervation, as no primary defects are expected to be present in muscles. So, the comparison between different animal models will provide important information about the mechanisms under evaluation.…”

Section: Discussionmentioning

confidence: 50%

Neuromuscular Plasticity in a Mouse Neurotoxic Model of Spinal Motoneuronal Loss

Gulino

Vicario

Giunta

et al. 2019

IJMS

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Despite the relevant research efforts, the causes of amyotrophic lateral sclerosis (ALS) are still unknown and no effective cure is available. Many authors suggest that ALS is a multi-system disease caused by a network failure instead of a cell-autonomous pathology restricted to motoneurons. Although motoneuronal loss is the critical hallmark of ALS given their specific vulnerability, other cell populations, including muscle and glial cells, are involved in disease onset and progression, but unraveling their specific role and crosstalk requires further investigation. In particular, little is known about the plastic changes of the degenerating motor system. These spontaneous compensatory processes are unable to halt the disease progression, but their elucidation and possible use as a therapeutic target represents an important aim of ALS research. Genetic animal models of disease represent useful tools to validate proven hypotheses or to test potential therapies, and the conception of novel hypotheses about ALS causes or the study of pathogenic mechanisms may be advantaged by the use of relatively simple in vivo models recapitulating specific aspects of the disease, thus avoiding the inclusion of too many confounding factors in an experimental setting. Here, we used a neurotoxic model of spinal motoneuron depletion induced by injection of cholera toxin-B saporin in the gastrocnemius muscle to investigate the possible occurrence of compensatory changes in both the muscle and spinal cord. The results showed that, following the lesion, the skeletal muscle became atrophic and displayed electromyographic activity similar to that observed in ALS patients. Moreover, the changes in muscle fiber morphology were different from that observed in ALS models, thus suggesting that some muscular effects of disease may be primary effects instead of being simply caused by denervation. Notably, we found plastic changes in the surviving motoneurons that can produce a functional restoration probably similar to the compensatory changes occurring in disease. These changes could be at least partially driven by glutamatergic signaling, and astrocytes contacting the surviving motoneurons may support this process.

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“…Deficiency in caspase-1 and IL-1b, as well as treatment with the recombinant IL-1 receptor antagonist anakinra, all significantly extended the lifespan of mutant SOD1 transgenic animals (Meissner et al, 2010). Consistently, the expression of NLRP3, NLRC4, AIM2, and caspase-1 activation has been demonstrated in neural tissue of mutant SOD1 transgenic animals (Pasinelli et al, 1998;Johann et al, 2015;Gugliandolo et al, 2018), and mutant SOD1 was shown to activate caspase-1 and IL-1b in microglia (Meissner et al, 2010;Lehmann et al, 2018). Increased caspase-1 levels have also been detected in serum of ALS patients (Ił _ zecka et al, 2001), and analysis of postmortem spinal cord tissue showed increased NLRP3, ASC, caspase-1, and IL-18 expression levels, with spinal cord astrocytes identified as the main NLRP3 inflammasome-expressing cell type (Johann et al, 2015).…”

Section: Inflammasome Activation In Amyotrophic Lateral Sclerosismentioning

confidence: 74%

Inflammasomes in neuroinflammatory and neurodegenerative diseases

et al. 2019

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Neuroinflammation and neurodegeneration often result from the aberrant deposition of aggregated host proteins, including amyloid‐β, α‐synuclein, and prions, that can activate inflammasomes. Inflammasomes function as intracellular sensors of both microbial pathogens and foreign as well as host‐derived danger signals. Upon activation, they induce an innate immune response by secreting the inflammatory cytokines interleukin ( IL )‐1β and IL ‐18, and additionally by inducing pyroptosis, a lytic cell death mode that releases additional inflammatory mediators. Microglia are the prominent innate immune cells in the brain for inflammasome activation. However, additional CNS ‐resident cell types including astrocytes and neurons, as well as infiltrating myeloid cells from the periphery, express and activate inflammasomes. In this review, we will discuss current understanding of the role of inflammasomes in common degenerative diseases of the brain and highlight inflammasome‐targeted strategies that may potentially treat these diseases.

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Expression profile of pattern recognition receptors in skeletal muscle of SOD1^(G93A) amyotrophic lateral sclerosis (ALS) mice and sporadic ALS patients

Abstract: Our findings suggest that increased inflammasome activation may be involved in skeletal muscle pathology in ALS. Furthermore, elevated levels of NLRC4, caspase 1 and IL1β reflect early changes in the skeletal muscle and may contribute to the denervation process.

Cited by 29 publications

References 127 publications

Neuroprotective Fragment C of Tetanus Toxin Modulates IL-6 in an ALS Mouse Model

Neuroprotective Fragment C of Tetanus Toxin Modulates IL-6 in an ALS Mouse Model

Neuromuscular Plasticity in a Mouse Neurotoxic Model of Spinal Motoneuronal Loss

Inflammasomes in neuroinflammatory and neurodegenerative diseases

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Expression profile of pattern recognition receptors in skeletal muscle of SOD1(G93A) amyotrophic lateral sclerosis (ALS) mice and sporadic ALS patients

Abstract: Our findings suggest that increased inflammasome activation may be involved in skeletal muscle pathology in ALS. Furthermore, elevated levels of NLRC4, caspase 1 and IL1β reflect early changes in the skeletal muscle and may contribute to the denervation process.

Cited by 29 publications

References 127 publications

Neuroprotective Fragment C of Tetanus Toxin Modulates IL-6 in an ALS Mouse Model

Neuroprotective Fragment C of Tetanus Toxin Modulates IL-6 in an ALS Mouse Model

Neuromuscular Plasticity in a Mouse Neurotoxic Model of Spinal Motoneuronal Loss

Inflammasomes in neuroinflammatory and neurodegenerative diseases

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Product

Resources

About

Expression profile of pattern recognition receptors in skeletal muscle of SOD1^(G93A) amyotrophic lateral sclerosis (ALS) mice and sporadic ALS patients