Abstract
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.
Highlights
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by the loss of the cortex, brainstem, and spinal cord motor neurons (MNs)
The interleukins most frequently found dysregulated in ALS were interleukin (IL)-2, IL-6 and IL-17 [5], there are some controversial results that question the role of these cytokines as reliable biomarkers
We studied the effect of a tetanus toxin C fragment protein (TTC)-based therapy in the SOD1G93A transgenic mice on the regulation of several pro-inflammatory mediators in plasma, and on NLRP3 inflammasome proteins in blood and two of the most affected tissues in the disease: spinal cord and skeletal muscle
Summary
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by the loss of the cortex, brainstem, and spinal cord motor neurons (MNs). This motoneuron degeneration leads to muscle paralysis and, premature death due to respiratory failure within 2–5 years after diagnosis. The interleukins most frequently found dysregulated in ALS were interleukin (IL)-2, IL-6 and IL-17 [5], there are some controversial results that question the role of these cytokines as reliable biomarkers Another mechanism associated with the immune system, the NLRP3 inflammasome, has been studied in ALS, showing its involvement in the disease [6,7,8]. The cause of the participation of NLRP3 inflammasome in ALS could underlie in the misfolded protein aggregates found in ALS, as they could become damage-associated molecular patterns (DAMPs) and cause direct activation of NLRP3, following the activation of cytokines [10]
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