Microglia and Other Myeloid Cells in Central Nervous System Health and Disease

Abstract

Mononuclear macrophages derived from the bone marrow (myeloid cells) are key cellular components of the innate immune system in different organs. In this minireview, we are focused on both brain and blood macrophages, known as microglia and monocytes, respectively. We provide a succinct summary of the cells' functions under both normal and pathologic conditions, with particular reference to common neurodegenerative disorders, such as Alzheimer and Parkinson disease. SIGNIFICANCE STATEMENT: In this minireview, we aim to summarize available literature on microglial and myeloid involvement in CNS disease, directing the reader toward relevant and translatable interpretations of myeloid cell function in CNS health and neurodegeneration.

Fig. 1.

Microglia at resting, activated, and dystrophic states are seen in MCAO (middle cerebral artery occlusion) unilateral stroke model brain tissue, accompanied by extensive peripheral myeloid cell infiltration. Within a coronal brain section from a mouse at 24 hours after the stroke in the contralateral hemisphere, (A) resting microglia are labeled with myeloid cell marker IBA1 (gray) and a marker of phagocytic and lysosomal function, CD68 (brown). (B) In the ipsilateral hemisphere, activated microglia at the edge of the lesion display a characteristic phenotype with increased IBA1 and CD68 expression, indicating active phagocytosis. (C) Dystrophic, fragmenting microglia can be observed within the stroke core. In addition to microglial activation, lesioned CNS tissue displays (D) extensive peripheral myeloid cell infiltration shown by Ly6B.2 immunostaining, specific to infiltrating peripheral myeloid cells. Identification of myeloid cell subtypes can be made using nuclear Nissl counterstain, as monocytes (mononuclear) or neutrophils (polymorphonuclear). Original magnification, 40× images. Scale bar, 20 μm.

Fig. 2.

Microglia and myeloid cell states in health and disease. While at homeostasis, (A) microglial activation in the CNS and alterations in peripheral blood myeloid cells are seldom seen, and dramatic changes in immune activation are seen in degenerative diseases such as AD and PD. (B) In AD, microglia become activated in response to amyloid formation and form phagocytic clusters attempting to remove this insoluble material. Neurofibrillary degeneration does not elicit microglial activation but coincides with microglial dystrophy; (C) in PD microglial activation, phagocytic activity and secretion of soluble signaling molecules are associated with response to dopaminergic neurons undergoing necroptosis in the midbrain. Secreted chemical factors also induce changes in peripheral myeloid populations, altering peripheral immune function and potentially inducing peripheral myeloid participation in dopaminergic degeneration.