Metabolic Reprograming of Mononuclear Phagocytes in Progressive Multiple Sclerosis

Abstract

Multiple sclerosis (MS) is an inflammatory and demyelinating disease of the central nervous system (CNS). Accumulation of brain damage in progressive MS is partly the result of mononuclear phagocytes (MPs) attacking myelin sheaths in the CNS. Although there is no cure yet for MS, significant advances have been made in the development of disease modifying agents. Unfortunately, most of these drugs fail to reverse established neurological deficits and can have adverse effects. Recent evidence suggests that MPs polarization is accompanied by profound metabolic changes, whereby pro-inflammatory MPs (M1) switch toward glycolysis, whereas anti-inflammatory MPs (M2) become more oxidative. It is therefore possible that reprograming MPs metabolism could affect their function and repress immune cell activation. This mini review describes the metabolic changes underpinning macrophages polarization and anticipates how metabolic re-education of MPs could be used for the treatment of MS.Key points: Inflammation in progressive MS is mediated primarily by MPs.Cell metabolism regulates the function of MPs.DMAs can re-educate the metabolism of MPs to promote healing.

Hyperpolarized 13 C MR metabolic imaging can detect neuroinflammation in vivo in a multiple sclerosis murine model

“…For instance, after W6 of CPZ administration we observed a strong reduction of MPs in the corpus callosum. Although most of the remaining MPs still express PDK1 and there is a trend toward decreased PDH activity compared with CTRL, we did not detect a significantly increased production of HP [1][2][3][4][5][6][7][8][9][10][11][12][13] C]lactate at that time point, which may be explained by the limited sensitivity of HP 13 C MRSI to lower MP number. Furthermore, the lack of increase in the HP [1-13 C]lactate-topyruvate ratios in two of seven mice at W4 (Fig.…”

“…Several recent studies have demonstrated that, upon activation and differentiation toward a proinflammatory phenotype, MPs undergo metabolic reprogramming toward enhanced glucose uptake and increased glycolysis (9)(10)(11)(12)(13)(14). As for the Warburg effect observed in cancer cells, this augmented glycolysis takes place under aerobic conditions and results in the majority of pyruvate being converted to lactate (15).…”

A parasite-derived 68-mer peptide ameliorates autoimmune disease in murine models of Type 1 diabetes and multiple sclerosis

“…In particular, the differentiation of macrophages towards a pro-inflammatory M1 phenotype underpins the pathophysiology of many autoimmune conditions, including MS, T1D, rheumatoid arthritis, and inflammatory bowel disease2829. Inhibition of macrophage function is sufficient to protect mice from auto-reactive T cell driven immune disorders, and elimination of M1 macrophages, or specific inhibition of their pro-inflammatory cytokine production, prevents autoimmune disease in murine models of MS3031 and T1D3233. As such, macrophages are the central regulators among immune cells determining if autoimmunity is initiated or prevented.…”

How to reprogram microglia toward beneficial functions

“…Dimethylfumarate (DMF) is an approved drug for MS, known to switch pro‐inflammatory microglia to a neuroprotective state (Parodi et al, ) and to reduce disease progression via activation of (erythroid‐derived 2)‐related factor‐2 (Nrf2), a transcription factor with antioxidant properties (Liddell, ). DMF has been proposed to exert its therapeutic effects modulating oxidative phosphorylation, through increased levels of the TCA cycle intermediate fumarate in microglia (Tannahill, Iraci, Gaude, Frezza, & Pluchino, ); (Figure ). However, this intriguing hypothesis still remains to be validated.…”