Metabolic Reprogramming in Progressive MS: Targeting Mononuclear Phagocytes for Therapy

Multiple sclerosis (MS) is a chronic, inflammatory, and demyelinating disease of the central nervous system (CNS). Characterized by episodes of neurological dysfunction and subsequent recovery, MS can progress to a stage marked by continuous degeneration and accumulation of disability. The disease is driven by immune cells attacking myelin sheaths, resulting in significant damage to neurons and axons. Among these immune cells, mononuclear phagocytes (MPs) such as microglia and macrophages play a crucial role in the pathology of MS, especially in its progressive form.

Role of Mononuclear Phagocytes in MS
MPs, including microglia and macrophages, are essential components of the immune system in the CNS. These cells are involved in homeostatic functions like clearing apoptotic cells and debris. Microglia are derived from yolk-sac blood islands during early development, while macrophages originate from bone marrow-derived hematopoietic stem cells. Despite their different origins, both cell types are pivotal in maintaining CNS health and responding to injury or infection.

In the context of MS, MPs are classified into two phenotypes based on their function and response to stimuli: M1 (pro-inflammatory) and M2 (anti-inflammatory). M1 MPs produce neurotoxic molecules and pro-inflammatory cytokines, contributing to tissue damage, whereas M2 MPs secrete growth factors and support tissue repair. The balance between these phenotypes is crucial for CNS homeostasis, and its disruption leads to the progression of MS.

Metabolic Reprogramming of MPs
Recent research has highlighted the significant metabolic changes that accompany MP activation and polarization. Pro-inflammatory M1 MPs rely on glycolysis for energy, a shift known as the Warburg effect, whereas anti-inflammatory M2 MPs utilize oxidative phosphorylation and fatty acid oxidation. This metabolic reprogramming is not just a consequence of activation but also a driver of the functional state of MPs.

Hypoxia and MP Activation
Hypoxia, or low oxygen levels, is a common feature in inflammatory sites within the CNS during MS. This hypoxic environment stabilizes hypoxia-inducible factor (HIF)-1α, a transcription factor that promotes glycolysis and the expression of pro-inflammatory cytokines such as IL-1β. Studies have shown that hypoxia-induced HIF-1α plays a crucial role in sustaining the glycolytic switch in activated MPs, contributing to chronic inflammation in MS.

Mitochondrial Metabolites in MP Function
Mitochondrial dysfunction in MPs during MS leads to the accumulation of specific metabolites like succinate, which stabilizes HIF-1α even in the presence of oxygen. This phenomenon, known as pseudohypoxia, further promotes the inflammatory state of MPs. Additionally, other metabolites such as itaconate and citrate have been implicated in regulating the inflammatory pathways in MPs. These metabolites not only serve as energy sources but also modulate immune responses.

Metabolic Re-education of MPs
Given the pivotal role of metabolism in MP function, targeting metabolic pathways to shift MPs from an M1 to an M2 phenotype presents a promising therapeutic strategy for MS. For example, activating AMP-activated kinase (AMPK) has been shown to promote an M2-like phenotype by enhancing oxidative metabolism. Metformin and AICAR, known AMPK activators, have demonstrated potential in reducing inflammation and disease progression in animal models of MS.

Dimethyl Fumarate and MP Metabolism
Dimethyl fumarate (DMF), an oral treatment for relapsing MS, exemplifies the therapeutic potential of targeting MP metabolism. DMF promotes a shift from a pro-inflammatory to an anti-inflammatory cytokine profile in immune cells. In animal models, DMF has been shown to reduce the presence of pro-inflammatory MPs in the CNS and to inhibit their activation in vitro. The exact mechanisms are still under investigation, but it is postulated that DMF may exert its effects by altering MP metabolism, favoring an anti-inflammatory state.

Conclusion
The intricate relationship between metabolism and immune function in MPs is a critical area of research in understanding and treating progressive MS. By elucidating the metabolic pathways that drive MP activation and polarization, novel therapeutic strategies can be developed to reprogram these cells towards a reparative phenotype, potentially halting or even reversing the progression of MS.

References
Tannahill, G. M., Iraci, N., Gaude, E., Frezza, C., & Pluchino, S. (2015). Metabolic reprograming of mononuclear phagocytes in progressive multiple sclerosis. Frontiers in immunology, 6, 106.