Differential roles of microglia and monocytes in the inflamed central nervous system

TLDR

In multiple sclerosis and its experimental model EAE, macrophages dominate demyelinated lesions, arise from either infiltrating monocytes or resident microglia, and their T‑cell‑driven activation drives inflammatory demyelination, yet the precise mechanisms of tissue injury remain poorly understood. The study aimed to distinguish the cellular origins of effector macrophages in autoimmune demyelination, separating microglial from monocyte‑derived populations. Using serial block‑face scanning electron microscopy, the authors mapped monocyte‑derived macrophages to nodes of Ranvier where they initiate demyelination, while microglia mainly clear debris. Gene‑expression analysis revealed monocyte‑derived macrophages are highly phagocytic and inflammatory, whereas microglia‑derived macrophages exhibit globally suppressed metabolism at disease onset, suggesting that targeting these distinct populations could inform new treatments and promote repair in inflammatory diseases.

Abstract

In the human disorder multiple sclerosis (MS) and in the model experimental autoimmune encephalomyelitis (EAE), macrophages predominate in demyelinated areas and their numbers correlate to tissue damage. Macrophages may be derived from infiltrating monocytes or resident microglia, yet are indistinguishable by light microscopy and surface phenotype. It is axiomatic that T cell–mediated macrophage activation is critical for inflammatory demyelination in EAE, yet the precise details by which tissue injury takes place remain poorly understood. In the present study, we addressed the cellular basis of autoimmune demyelination by discriminating microglial versus monocyte origins of effector macrophages. Using serial block-face scanning electron microscopy (SBF-SEM), we show that monocyte-derived macrophages associate with nodes of Ranvier and initiate demyelination, whereas microglia appear to clear debris. Gene expression profiles confirm that monocyte-derived macrophages are highly phagocytic and inflammatory, whereas those arising from microglia demonstrate an unexpected signature of globally suppressed cellular metabolism at disease onset. Distinguishing tissue-resident macrophages from infiltrating monocytes will point toward new strategies to treat disease and promote repair in diverse inflammatory pathologies in varied organs.