Carnosine quenches the reactive carbonyl acrolein in the central nervous system and attenuates autoimmune neuroinflammation
Abstract Background Multiple sclerosis (MS) is a chronic autoimmune disease driven by sustained inflammation in the central nervous system. One of the pathological hallmarks of MS is extensive free radical production. However, the subsequent generation, potential pathological role, and detoxificatio...
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2021
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oai:doaj.org-article:3715f5de65d64b1e9a2469cd2e5cb2442021-11-08T11:14:13ZCarnosine quenches the reactive carbonyl acrolein in the central nervous system and attenuates autoimmune neuroinflammation10.1186/s12974-021-02306-91742-2094https://doaj.org/article/3715f5de65d64b1e9a2469cd2e5cb2442021-11-01T00:00:00Zhttps://doi.org/10.1186/s12974-021-02306-9https://doaj.org/toc/1742-2094Abstract Background Multiple sclerosis (MS) is a chronic autoimmune disease driven by sustained inflammation in the central nervous system. One of the pathological hallmarks of MS is extensive free radical production. However, the subsequent generation, potential pathological role, and detoxification of different lipid peroxidation-derived reactive carbonyl species during neuroinflammation are unclear, as are the therapeutic benefits of carbonyl quenchers. Here, we investigated the reactive carbonyl acrolein and (the therapeutic effect of) acrolein quenching by carnosine during neuroinflammation. Methods The abundance and localization of acrolein was investigated in inflammatory lesions of MS patients and experimental autoimmune encephalomyelitis (EAE) mice. In addition, we analysed carnosine levels and acrolein quenching by endogenous and exogenous carnosine in EAE. Finally, the therapeutic effect of exogenous carnosine was assessed in vivo (EAE) and in vitro (primary mouse microglia, macrophages, astrocytes). Results Acrolein was substantially increased in inflammatory lesions of MS patients and EAE mice. Levels of the dipeptide carnosine (β-alanyl-l-histidine), an endogenous carbonyl quencher particularly reactive towards acrolein, and the carnosine-acrolein adduct (carnosine-propanal) were ~ twofold lower within EAE spinal cord tissue. Oral carnosine treatment augmented spinal cord carnosine levels (up to > tenfold), increased carnosine-acrolein quenching, reduced acrolein-protein adduct formation, suppressed inflammatory activity, and alleviated clinical disease severity in EAE. In vivo and in vitro studies indicate that pro-inflammatory microglia/macrophages generate acrolein, which can be efficiently quenched by increasing carnosine availability, resulting in suppressed inflammatory activity. Other properties of carnosine (antioxidant, nitric oxide scavenging) may also contribute to the therapeutic effects. Conclusions Our results identify carbonyl (particularly acrolein) quenching by carnosine as a therapeutic strategy to counter inflammation and macromolecular damage in MS.Jan SpaasWouter M. A. FranssenCharly KeytsmanLaura BlancquaertTim VanmierloJeroen BogieBieke BrouxNiels HellingsJack van HorssenDheeraj Kumar PosaDavid HoetkerShahid P. BabaWim DeraveBert O. EijndeBMCarticleAcroleinCarnosineMultiple sclerosisNeuroinflammationOxidative stressReactive carbonylNeurology. Diseases of the nervous systemRC346-429ENJournal of Neuroinflammation, Vol 18, Iss 1, Pp 1-19 (2021) |
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DOAJ |
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| language |
EN |
| topic |
Acrolein Carnosine Multiple sclerosis Neuroinflammation Oxidative stress Reactive carbonyl Neurology. Diseases of the nervous system RC346-429 |
| spellingShingle |
Acrolein Carnosine Multiple sclerosis Neuroinflammation Oxidative stress Reactive carbonyl Neurology. Diseases of the nervous system RC346-429 Jan Spaas Wouter M. A. Franssen Charly Keytsman Laura Blancquaert Tim Vanmierlo Jeroen Bogie Bieke Broux Niels Hellings Jack van Horssen Dheeraj Kumar Posa David Hoetker Shahid P. Baba Wim Derave Bert O. Eijnde Carnosine quenches the reactive carbonyl acrolein in the central nervous system and attenuates autoimmune neuroinflammation |
| description |
Abstract Background Multiple sclerosis (MS) is a chronic autoimmune disease driven by sustained inflammation in the central nervous system. One of the pathological hallmarks of MS is extensive free radical production. However, the subsequent generation, potential pathological role, and detoxification of different lipid peroxidation-derived reactive carbonyl species during neuroinflammation are unclear, as are the therapeutic benefits of carbonyl quenchers. Here, we investigated the reactive carbonyl acrolein and (the therapeutic effect of) acrolein quenching by carnosine during neuroinflammation. Methods The abundance and localization of acrolein was investigated in inflammatory lesions of MS patients and experimental autoimmune encephalomyelitis (EAE) mice. In addition, we analysed carnosine levels and acrolein quenching by endogenous and exogenous carnosine in EAE. Finally, the therapeutic effect of exogenous carnosine was assessed in vivo (EAE) and in vitro (primary mouse microglia, macrophages, astrocytes). Results Acrolein was substantially increased in inflammatory lesions of MS patients and EAE mice. Levels of the dipeptide carnosine (β-alanyl-l-histidine), an endogenous carbonyl quencher particularly reactive towards acrolein, and the carnosine-acrolein adduct (carnosine-propanal) were ~ twofold lower within EAE spinal cord tissue. Oral carnosine treatment augmented spinal cord carnosine levels (up to > tenfold), increased carnosine-acrolein quenching, reduced acrolein-protein adduct formation, suppressed inflammatory activity, and alleviated clinical disease severity in EAE. In vivo and in vitro studies indicate that pro-inflammatory microglia/macrophages generate acrolein, which can be efficiently quenched by increasing carnosine availability, resulting in suppressed inflammatory activity. Other properties of carnosine (antioxidant, nitric oxide scavenging) may also contribute to the therapeutic effects. Conclusions Our results identify carbonyl (particularly acrolein) quenching by carnosine as a therapeutic strategy to counter inflammation and macromolecular damage in MS. |
| format |
article |
| author |
Jan Spaas Wouter M. A. Franssen Charly Keytsman Laura Blancquaert Tim Vanmierlo Jeroen Bogie Bieke Broux Niels Hellings Jack van Horssen Dheeraj Kumar Posa David Hoetker Shahid P. Baba Wim Derave Bert O. Eijnde |
| author_facet |
Jan Spaas Wouter M. A. Franssen Charly Keytsman Laura Blancquaert Tim Vanmierlo Jeroen Bogie Bieke Broux Niels Hellings Jack van Horssen Dheeraj Kumar Posa David Hoetker Shahid P. Baba Wim Derave Bert O. Eijnde |
| author_sort |
Jan Spaas |
| title |
Carnosine quenches the reactive carbonyl acrolein in the central nervous system and attenuates autoimmune neuroinflammation |
| title_short |
Carnosine quenches the reactive carbonyl acrolein in the central nervous system and attenuates autoimmune neuroinflammation |
| title_full |
Carnosine quenches the reactive carbonyl acrolein in the central nervous system and attenuates autoimmune neuroinflammation |
| title_fullStr |
Carnosine quenches the reactive carbonyl acrolein in the central nervous system and attenuates autoimmune neuroinflammation |
| title_full_unstemmed |
Carnosine quenches the reactive carbonyl acrolein in the central nervous system and attenuates autoimmune neuroinflammation |
| title_sort |
carnosine quenches the reactive carbonyl acrolein in the central nervous system and attenuates autoimmune neuroinflammation |
| publisher |
BMC |
| publishDate |
2021 |
| url |
https://doaj.org/article/3715f5de65d64b1e9a2469cd2e5cb244 |
| work_keys_str_mv |
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1718442321052172288 |