Abstract
Clinical symptom worsening in patients with multiple sclerosis (MS) is driven by inflammation compartmentalized within the CNS, which results in chronic neuronal damage owing to insufficient repair mechanisms. The term ‘smouldering inflammation’ summarizes the biological aspects underlying this chronic, non-relapsing and immune-mediated mechanism of disease progression. Smouldering inflammation is likely to be shaped and sustained by local factors in the CNS that account for the persistence of this inflammatory response and explain why current treatments for MS do not sufficiently target this process. Local factors that affect the metabolic properties of glial cells and neurons include cytokines, pH value, lactate levels and nutrient availability. This Review summarizes current knowledge of the local inflammatory microenvironment in smouldering inflammation and how it interacts with the metabolism of tissue-resident immune cells, thereby promoting inflammatory niches within the CNS. The discussion highlights environmental and lifestyle factors that are increasingly recognized as capable of altering immune cell metabolism and potentially responsible for smouldering pathology in the CNS. Currently approved MS therapies that target metabolic pathways are also discussed, along with their potential for preventing the processes that contribute to smouldering inflammation and thereby to progressive neurodegenerative damage in MS.
Key points
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The term ‘smouldering inflammation’ summarizes the biological aspects that underlie compartmentalized CNS inflammation and chronic neuronal damage, which are insufficiently targeted by currently approved therapies.
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The chronically inflamed CNS provides a unique tissue microenvironment characterized by alterations in nutrient availability, pH value, lactate levels and cytokine profiles.
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Tissue-resident memory T cells, microglia and astrocytes are key immune cells in smouldering inflammation that can adapt their metabolic profiles in response to the inflamed microenvironment.
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Environmental and lifestyle factors are increasingly recognized as modulators of immune cell metabolism.
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Modulation of immune cell metabolism and the inflammatory microenvironment might foster novel treatment approaches in smouldering inflammation.
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Acknowledgements
The authors’ research work is supported by grants from the German Research Council (DFG): CRC-TR-128 to F.Z. and S.B.; CRC-TR-355 to S.B.; CRC1080 and SFB1292 to F.Z.; the Progressive Multiple Sclerosis Alliance (PMSA): BRAVEinMS PA-1604–08492 to F.Z.; and the Herman and Lilly Schilling Foundation to S.B. The authors thank C. Ernest for proofreading and editing the manuscript.
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S.B., K.P. and F.Z. wrote the manuscript. S.B., K.P. and L.K. researched data for the article. All authors contributed substantially to discussions of the content and to review and/or editing of the manuscript before submission.
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S.B. declares that he has received honoraria from Biogen Idec, Bristol Meyers Squibb, Merck Healthcare, Novartis, Sanofi, Roche and Teva. F.Z. declares that she has received research grants and/or consultation funds from Biogen, Ministry of Education and Research (BMBF), Bristol Meyers Squibb, Celgene, German Research Foundation (DFG), Janssen, the Max Planck Society (MPG), Merck Serono, Novartis, Progressive MS Alliance (PMSA), Roche, Sandoz and Sanofi Genzyme. K.P. and L.K. declare no competing interests.
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Nature Reviews Neurology thanks Lars Fugger, Bianca Weinstock-Guttman and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
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Glossary
- Aerobic glycolysis
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The pathway that converts pyruvate into lactate in an aerobic environment and generates NAD+ molecules.
- Experimental autoimmune encephalomyelitis
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(EAE). The most common experimental animal model of multiple sclerosis; inflammatory demyelinating brain disease can be induced in various animal species and strains by different methods depending on the experimental question.
- Fatty acid oxidation
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The metabolic pathway that converts fatty acids to acetyl coenzyme A to fuel the tricarboxylic acid cycle.
- Glutaminolysis
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The metabolic pathway that converts glutamine to α-ketoglutarate to fuel the tricarboxylic acid cycle.
- Glycolysis
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An oxygen-independent metabolic pathway that rapidly converts glucose into pyruvate to produce ATP and several metabolic intermediates used in further pathways.
- Immunometabolism
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The interplay between metabolism and immunology in both health and disease.
- Oxidative phosphorylation
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The metabolic pathway in which substrates are oxidized in the tricarboxylic acid cycle to generate ATP via the mitochondrial electron transport chain.
- Smouldering inflammation
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An umbrella term that includes all CNS-intrinsic, non-relapsing inflammatory processes in patients with multiple sclerosis such as chronically active lesions, diffuse alterations of the grey matter and normal-appearing white matter, meningeal inflammation, and cortical inflammation.
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Bittner, S., Pape, K., Klotz, L. et al. Implications of immunometabolism for smouldering MS pathology and therapy. Nat Rev Neurol 19, 477–488 (2023). https://doi.org/10.1038/s41582-023-00839-6
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DOI: https://doi.org/10.1038/s41582-023-00839-6
