Implications of immunometabolism for smouldering MS pathology and therapy

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. Smouldering inflammation encompasses all non-relapsing aspects of inflammatory pathobiology in multiple sclerosis. Here, Bittner and colleagues describe the mechanisms that underlie CNS-compartmentalized smouldering inflammation and review evidence indicating that immunometabolic reprogramming driven by the CNS tissue microenvironment shapes these inflammatory responses. Potential treatments are also discussed.

Automated summary

Worsening clinical symptoms in patients with multiple sclerosis (MS) are caused by inflammation specifically occurring within the CNS. This chronic and non-relapsing immune-mediated mechanism of disease progression, called "smouldering inflammation," is sustained by local factors in the CNS and explains why current MS treatments do not adequately target it. This review summarizes the current understanding of the local inflammatory microenvironment in smouldering inflammation, its interaction with immune cell metabolism, and potential treatments for preventing neurodegenerative damage.