Carnosine quenches the reactive carbonyl acrolein in the central nervous system and attenuates autoimmune neuroinflammation

Journal of Neuroinflammation

Wouter M. A. Franssen¹  Wim Derave²  Laura Blancquaert²  Shahid P. Baba³  David Hoetker³  Dheeraj Kumar Posa³  Bert O. Eijnde⁴  Jeroen Bogie⁴  Jack van Horssen⁵  Jan Spaas⁶  Charly Keytsman⁷  Niels Hellings⁸  Bieke Broux⁹  Tim Vanmierlo^1,10 

[1] BIOMED Biomedical Research Institute, Faculty of Medicine and Life Sciences, Hasselt University, Hasselt, Belgium;REVAL Rehabilitation Research Center, Faculty of Rehabilitation Sciences, Hasselt University, Hasselt, Belgium;Department of Movement and Sports Sciences, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium;Diabetes and Obesity Center, University of Louisville, Louisville, KY, USA;University MS Center (UMSC) Hasselt – Pelt, Hasselt, Belgium;BIOMED Biomedical Research Institute, Faculty of Medicine and Life Sciences, Hasselt University, Hasselt, Belgium;University MS Center (UMSC) Hasselt – Pelt, Hasselt, Belgium;BIOMED Biomedical Research Institute, Faculty of Medicine and Life Sciences, Hasselt University, Hasselt, Belgium;Department of Molecular Cell Biology and Immunology, Amsterdam Neuroscience, MS Center Amsterdam, Amsterdam University Medical Center, Location VUmc, Amsterdam, The Netherlands;University MS Center (UMSC) Hasselt – Pelt, Hasselt, Belgium;BIOMED Biomedical Research Institute, Faculty of Medicine and Life Sciences, Hasselt University, Hasselt, Belgium;Department of Movement and Sports Sciences, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium;University MS Center (UMSC) Hasselt – Pelt, Hasselt, Belgium;BIOMED Biomedical Research Institute, Faculty of Medicine and Life Sciences, Hasselt University, Hasselt, Belgium;REVAL Rehabilitation Research Center, Faculty of Rehabilitation Sciences, Hasselt University, Hasselt, Belgium;University MS Center (UMSC) Hasselt – Pelt, Hasselt, Belgium;Neuro-Immune Connections and Repair Lab, Department of Immunology and Infection, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium;University MS Center (UMSC) Hasselt – Pelt, Hasselt, Belgium;Neuro-Immune Connections and Repair Lab, Department of Immunology and Infection, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium;Department of Internal Medicine, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands;University MS Center (UMSC) Hasselt – Pelt, Hasselt, Belgium;Neuro-Immune Connections and Repair Lab, Department of Immunology and Infection, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium;Division of Translational Neuroscience, Department Psychiatry and Neuropsychology, European Graduate School of Neuroscience, School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands;

关键词: Acrolein;    Carnosine;    Multiple sclerosis;    Neuroinflammation;    Oxidative stress;    Reactive carbonyl;   

DOI  :  10.1186/s12974-021-02306-9

来源: Springer

【 摘 要 】

BackgroundMultiple 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.MethodsThe 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).ResultsAcrolein 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.ConclusionsOur results identify carbonyl (particularly acrolein) quenching by carnosine as a therapeutic strategy to counter inflammation and macromolecular damage in MS.

【 授权许可】

CC BY