Role of IL-33/ST2-dependent regulation of microglial function in Alzheimer's disease

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disease and the leading cause of dementia. Abnormal production and accumulation of amyloid-beta (Aβ) peptides are critical in the pathogenesis of AD. Increasing evidence indicates that microglia, which are the resident myeloid cells in the central nervous system, exert important effects on Aβ metabolism. Interleukin (IL)-33 ameliorates AD-like pathology by modulating microglial function in APP/PS1 mice, an AD transgenic mouse model. The present study showed that in APP/PS1 mice, IL-33 expression in the cortex is downregulated, whereas the microglial expression of its receptor, ST2, is upregulated. In addition, the ST2⁺ microglia subpopulation has higher Aβ uptake capacity, which is further promoted by IL-33 administration. These results indicate that IL-33/ST2 signaling is regulated during AD pathogenesis and promotes microglial Aβ uptake. RNA sequencing revealed that IL-33 alters the transcriptome profile of microglia in APP/PS1 mice, which is associated with inflammatory response and phagocytosis. Further analysis suggested that ST2⁺ microglia have higher CD14 and MHC II expression, which is correlated with microglial Aβ phagocytosis. Thus, the results collectively demonstrate how IL-33/ST2 signaling modulates microglia towards a beneficial phenotype characterized by higher Aβ phagocytic ability. Therefore, IL-33 could be developed as a therapeutic strategy for the treatment of AD.

Date of Award	2018
Original language	English
Awarding Institution	The Hong Kong University of Science and Technology