Cues of Trained Immunity in Multiple Sclerosis Macrophages

Abstract

Multiple sclerosis (MS) is a complex autoimmune disease with both genetic and environmental influences, yet its underlying mechanisms remain only partially understood. In this review, we compile evidence suggesting that trained immunity-a form of innate immune memory-may play a crucial role in the autoimmune component of MS. By examining key findings from immunology, neuroinflammation, and MS pathophysiology, we explore how innate immune cells, particularly monocytes and macrophages, could contribute to disease onset and progression through persistent pro-inflammatory responses. Understanding the impact of trained immunity in MS could open new avenues for therapeutic strategies targeting the innate immune system.

Keywords: epigenetic; inflammation; macrophages; metabolism; multiple sclerosis; trained immunity.

Figure 1

Functional and metabolic dysregulation of macrophages in MS patients and potential epigenetic rearrangements. On the left, macrophages from HCs exhibit balanced OXPHOS, effective phagocytosis with efficient clearance of myelin debris, and low CD16 expression. On the right, MS macrophages show increased CD16 expression, accumulation of myelin debris due to impaired phagocytosis, and a greater dependance on glycolysis and elevated cytokine secretion. This leads to a greater differentiation toward astrocytes rather than oligodendrocytes when glial progenitors are exposed to MS macrophages-conditioned media compared with HCs. This heightened inflammatory phenotype could be due to epigenetic rewiring (hypothesis illustrated in grey—Elisa). This scheme was created on Biorender https://biorender.com/.