IL-33-PU.1 Transcriptome Reprogramming Drives Functional State Transition and Clearance Activity of Microglia in Alzheimer’s Disease
Authors: Amy K Y Fu
Wing-Yu Fu
Congping Chen
Shun-Fat Lau
Jianan Y Qu
Nancy Y Ip
Tom H Cheung
Journal: Cell Reports (2020)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: MHC-II; PU.1; beta-amyloid; chemotaxis; chromatin accessibility
Affiliations: Division 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., State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China; Biophotonics Research Laboratory, Department of Electronic and Computer Engineering, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China; Center of Systems Biology and Human Health, School of Science and Institute for Advanced Study, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China., Division 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., Division 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; Guangdong Provincial Key Laboratory of Brain Science, Disease and Drug Development, HKUST Shenzhen Research Institute, Shenzhen-Hong Kong Institute of Brain Science, Shenzhen, Guangdong 518057, China., Division 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; Guangdong Provincial Key Laboratory of Brain Science, Disease and Drug Development, HKUST Shenzhen Research Institute, Shenzhen-Hong Kong Institute of Brain Science, Shenzhen, Guangdong 518057, China. Electronic address: .

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. 

Retracted: No

PubPeer comments:
 Figure 6I is one of the key data supporting the main conclusion. However, the experimental design of this critical experiment is not rigorous. 1. The mice they used were between 10 to 12 months of age. Because amyloid accumulation is progressive, mice at the same age should have been used. 2. Sex as a biological variable was not considered. Because this mouse model has sex-dependent differences in multiple phenotypes, sex should have been included in the analysis. 3. It is not described how  representative areas were selected and how many images were analyzed. Within 15 hours of IL-33 injection, amyloid plaque area was dramatically decreased. This finding is extraordinary and appears to be consistent with their earlier report in 2016 yr PNAS. https: pubmed.ncbi.nlm.nih.gov 27091974 ,