Multiple Sclerosis and Other Acquired Demyelinating Diseases of the Central Nervous System.

Acquired demyelinating diseases of the central nervous system (CNS) comprise inflammatory conditions, including multiple sclerosis (MS) and related diseases, as well as noninflammatory conditions caused by toxic, metabolic, infectious, traumatic, and neurodegenerative insults. Here, we review the spectrum of diseases producing acquired CNS demyelination before focusing on the prototypical example of MS, exploring the pathologic mechanisms leading to myelin injury in relapsing and progressive MS and summarizing the mechanisms and modulators of remyelination. We highlight the complex interplay between the immune system, oligodendrocytes and oligodendrocyte progenitor cells (OPCs), and other CNS glia cells such as microglia and astrocytes in the pathogenesis and clinical course of MS. Finally, we review emerging therapeutic strategies that exploit our growing understanding of disease mechanisms to limit progression and promote remyelination.

TPPB modulates PKC activity to attenuate neuroinflammation and ameliorate experimental multiple sclerosis.

Protein kinase C (PKC) plays a key role in modulating the activities of the innate immune cells of the central nervous system (CNS). A delicate balance between pro-inflammatory and regenerative activities by microglia and CNS-associated macrophages is necessary for the proper functioning of the CNS. Thus, a maladaptive activation of these CNS innate immune cells results in neurodegeneration and demyelination associated with various neurologic disorders, such as multiple sclerosis (MS) and Alzheimer's disease. Prior studies have demonstrated that modulation of PKC activity by bryostatin-1 (bryo-1) and its analogs (bryologs) attenuates the pro-inflammatory processes by microglia/CNS macrophages and alleviates the neurologic symptoms in experimental autoimmune encephalomyelitis (EAE), an MS animal model. Here, we demonstrate that (2S,5S)-(E,E)-8-(5-(4(trifluoromethyl)phenyl)-2,4-pentadienoylamino)benzolactam (TPPB), a structurally distinct PKC modulator, has a similar effect to bryo-1 on CNS innate immune cells both in vitro and in vivo, attenuating neuroinflammation and resulting in CNS regeneration and repair. This study identifies a new structural class of PKC modulators, which can therapeutically target CNS innate immunity as a strategy to treat neuroinflammatory and neurodegenerative disorders.

TPPB modulates PKC activity to attenuate neuroinflammation and ameliorate experimental multiple sclerosis.

Protein kinase C (PKC) plays a key role in modulating the activities of the innate immune cells of the central nervous system (CNS). A delicate balance between pro-inflammatory and regenerative activities by microglia and CNS-associated macrophages is necessary for the proper functioning of the CNS. Thus, a maladaptive activation of these CNS innate immune cells results in neurodegeneration and demyelination associated with various neurologic disorders, such as multiple sclerosis (MS) and Alzheimer's disease. Prior studies have demonstrated that modulation of PKC activity by bryostatin-1 (bryo-1) and its analogs (bryologs) attenuates the pro-inflammatory processes by microglia/CNS macrophages and alleviates the neurologic symptoms in experimental autoimmune encephalomyelitis (EAE), an MS animal model. Here, we demonstrate that (2S,5S)-(E,E)-8-(5-(4-(trifluoromethyl)phenyl)-2,4-pentadienoylamino)benzolactam (TPPB), a structurally distinct PKC modulator, has a similar effect to bryo-1 on CNS innate immune cells both in vitro and in vivo, attenuating neuroinflammation and resulting in CNS regeneration and repair. This study identifies a new structural class of PKC modulators, which can therapeutically target CNS innate immunity as a strategy to treat neuroinflammatory and neurodegenerative disorders.

Phosphoglycerate mutase regulates Treg differentiation through control of serine synthesis and one-carbon metabolism.

The differentiation and suppressive functions of regulatory CD4 T cells (Tregs) are supported by a broad array of metabolic changes, providing potential therapeutic targets for immune modulation. In this study, we focused on the regulatory role of glycolytic enzymes in Tregs and identified phosphoglycerate mutase (PGAM) as being differentially overexpressed in Tregs and associated with a highly suppressive phenotype. Pharmacologic or genetic inhibition of PGAM reduced Treg differentiation and suppressive function while reciprocally inducing markers of a pro-inflammatory, T helper 17 (Th17)-like state. The regulatory role of PGAM was dependent on the contribution of 3-phosphoglycerate (3PG), the PGAM substrate, to de novo serine synthesis. Blocking de novo serine synthesis from 3PG reversed the effect of PGAM inhibition on Treg polarization, while exogenous serine directly inhibited Treg polarization. Additionally, altering serine levels in vivo with a serine/glycine-free diet increased peripheral Tregs and attenuated autoimmunity in a murine model of multiple sclerosis. Mechanistically, we found that serine limits Treg polarization by contributing to one-carbon metabolism and methylation of Treg-associated genes. Inhibiting one-carbon metabolism increased Treg polarization and suppressive function both in vitro and in vivo in a murine model of autoimmune colitis. Our study identifies a novel physiologic role for PGAM and highlights the metabolic interconnectivity between glycolysis, serine synthesis, one-carbon metabolism, and epigenetic regulation of Treg differentiation and suppressive function.