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IL-33-PU.1 Transcriptome Reprogramming Drives Functional State Transition and Clearance Activity of Microglia in
Shun-Fat Lau1, Congping Chen2, Wing-Yu Fu1
1Division of Life Science, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China; State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China; Molecular Neuroscience Center, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China.
Abstract:
Impairment of microglial clearance activity contributes to beta-amyloid (Aβ) pathology in Alzheimer's disease (AD). While the transcriptome profile of microglia directs microglial functions, how the microglial transcriptome can be regulated to alleviate AD pathology is largely unknown. Here, we show that injection of interleukin (IL)-33 in an AD transgenic mouse model ameliorates Aβ pathology by reprogramming microglial epigenetic and transcriptomic profiles to induce a microglial subpopulation with enhanced phagocytic activity. These IL-33-responsive microglia (IL-33RMs) express a distinct transcriptome signature that is highlighted by increased major histocompatibility complex class II genes and restored homeostatic signature genes. IL-33-induced remodeling of chromatin accessibility and PU.1 transcription factor binding at the signature genes of IL-33RM control their transcriptome reprogramming. Specifically, disrupting PU.1-DNA interaction abolishes the microglial state transition and Aβ clearance that is induced by IL-33. Thus, we define a PU.1-dependent transcriptional pathway that drives the IL-33-induced functional state transition of microglia, resulting in enhanced Aβ clearance.
Insights
Interleukin-33 (IL-33) injection in Alzheimer's disease (AD) models enhances microglial clearance of beta-amyloid (Aβ) pathology. This occurs through reprogramming microglia into IL-33-responsive microglia (IL-33RMs) via a PU.1-dependent pathway.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Microglial dysfunction in clearing beta-amyloid (Aβ) is central to Alzheimer's disease (AD) pathology.
- Understanding microglial transcriptome regulation is key to developing AD therapies.
Purpose of the Study:
- To investigate if interleukin-33 (IL-33) can reprogram microglia to enhance Aβ clearance in AD models.
- To elucidate the epigenetic and transcriptomic mechanisms underlying IL-33-mediated microglial functional changes.
Main Methods:
- Administration of IL-33 to an AD transgenic mouse model.
- Analysis of microglial epigenetic and transcriptomic profiles.
- Investigation of transcription factor PU.1 binding and its role in microglial state transition.
Main Results:
- IL-33 injection ameliorated Aβ pathology in AD mice.
- IL-33 induced a subpopulation of microglia (IL-33RMs) with enhanced phagocytic activity.
- IL-33RMs exhibited a distinct transcriptome signature, including increased MHC class II and homeostatic genes, regulated by PU.1.
- Disruption of PU.1 binding abolished IL-33-induced microglial transition and Aβ clearance.
Conclusions:
- IL-33 effectively reprograms microglia to combat Aβ pathology in AD.
- A PU.1-dependent transcriptional pathway mediates IL-33-induced microglial functional reprogramming and enhanced Aβ clearance.
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