Microglia, the major resident immune cells in the brain, play a critical role in maintaining central nervous system homeostasis. Impaired microglial responses (i.e., chemotaxis and phagocytosis) toward damage-associated molecular patterns are associated with various neurodegenerative diseases including Alzheimer’s disease. While previous studies show that enhancing chemotactic and phagocytic responses in microglia ameliorates Alzheimer’s disease pathology, the molecular mechanisms that control these beneficial functions of microglia remain unclear. Using interleukin 33 (IL-33) as a model to promote these beneficial functions, we demonstrated that microglia undergo a stepwise functional state transition to a phagocytic state in APP/PS1 mice, a mouse model of amyloid deposition. These pha...[ Read more ]

Microglia, the major resident immune cells in the brain, play a critical role in maintaining central nervous system homeostasis. Impaired microglial responses (i.e., chemotaxis and phagocytosis) toward damage-associated molecular patterns are associated with various neurodegenerative diseases including Alzheimer’s disease. While previous studies show that enhancing chemotactic and phagocytic responses in microglia ameliorates Alzheimer’s disease pathology, the molecular mechanisms that control these beneficial functions of microglia remain unclear. Using interleukin 33 (IL-33) as a model to promote these beneficial functions, we demonstrated that microglia undergo a stepwise functional state transition to a phagocytic state in APP/PS1 mice, a mouse model of amyloid deposition. These phagocytic microglia, termed IL-33–responsive microglia (IL-33RM), express a distinct transcriptomic signature characterized by increased major histocompatibility complex class II genes and restored homeostatic signature genes. Epigenetic profiling revealed that the functional state transition is controlled by the remodeling of the chromatin accessibility landscape and PU.1-binding landscape. Blocking the transcriptional activity of PU.1 inhibited the induction of the phagocytic state and attenuated Aβ clearance after IL-33 treatment. Thus, my findings delineate the molecular and cellular mechanisms underlying the beneficial effects of IL-33 in Alzheimer’s disease. More importantly, my study identified novel molecular targets that can promote beneficial functions of microglia in Alzheimer’s disease.