Fig. 1: IL-33-responsive microglia undergo stepwise transcriptomic reprogramming.
From: The VCAM1–ApoE pathway directs microglial chemotaxis and alleviates Alzheimer’s disease pathology
a–c, IL-33 induces prolonged expression of the microglial chemotactic gene signature. a, Heatmap showing the expression levels of 1,433 IL-33-induced genes in microglia 3, 8 and 24 h after IL-33 treatment (adjusted P value < 0.05). The bar on the far right indicates genes showing transient activation (red) and prolonged activation (orange). b, Bar plot showing the top GO pathways associated with the genes showing transient (red) and prolonged (orange) activation (as in panel a). FDR, false discovery rate. c, Protein–protein interaction analysis of genes exhibiting prolonged activation. d–g, IL-33 regulates microglial heterogeneity in a sequential manner. d, Uniform Manifold Approximation and Projection (UMAP) plot of three microglial subtypes showing unbiased clustering of 72,519 microglia from APP/PS1 mice treated with IL-33 or control for 3, 8, or 24 h (each condition corresponds to 3 biological independent samples). e, Dot plot showing the expression levels of the top signature genes of the 3 microglial subtypes. f,g, UMAP plots (f) and bar plots (g) showing the proportions of homeostatic, chemotactic and DAM in the four conditions (n = 3 mice in each condition; one-way ANOVA with Dunnett’s multiple comparisons test). Con, control. h–j, The developmental lineage of IL-33RM involves the sequential homeostatic–chemotactic–phagocytic state transition. UMAP plots showing the cell trajectory (h) and pseudotime ordering (i) of the IL-33RM developmental lineage. j, Heatmap visualizing the smoothed expression levels of the top homeostatic, chemotactic, DAM, and phagocytic signature genes (as described in the text) along the IL-33RM developmental lineage. All data are mean ± standard error of the mean (s.e.m.).
