Single-cell transcriptome profiling reveals heterogeneity of brain myeloid cells and unique subsets that regulate T cell immunity and cerebrovascular inflammation in diet-induced obesity

Abstract

Abstract Midlife obesity and type 2 diabetes mellitus (T2DM) are linked to decreased cognition and strong risk for Alzheimer’s disease in late life. Previous studies show that obesity/T2DM is associated with a heightened state of neuroinflammation in aging mice. However, it remains unclear how diverse immune cell populations in the brain contribute to the cognitive decline. To address this, we fed middle-aged mice with high-fat diet (HFD) to induce visceral obesity and hyperglycemia. Chronic HFD consumption resulted in cognitive impairment and activation of brain resident microglia (MG). The CD45hiCD11b+ peripheral myeloid cells and CD3+ T cells were significantly increased in the brain of obese mice. Single-cell RNA sequencing was performed to characterize CD11b+ cells isolated from the brain. Unsupervised clustering singled out distinct myeloid cell clusters. Using Tmem119 and P2ry12 as markers to distinguish MG from infiltrating cells, we observed a 2-fold increase of peripheral myeloid cells, comprising distinct clusters in HFD-fed mice. Multiple subsets of MG were identified in HFD-fed mice, showing Ms4a, Apoe and gene signatures of perivascular macrophages. Notably, these subsets expressed high levels of MHC class-II-related molecules, H2-Eb1, H2-Ab1, and Cd74, and with special functions in lipid metabolism. These data suggested possible interactions between MG and T cells to potentiate neuroinflammation in HFD-fed mice. Overall, our results highlighted heterogeneity of brain myeloid cells in obesity during aging. The identified subsets of MG provide insights into brain MG controlling T cell immunity and cerebrovascular inflammation, which might lead to cognitive impairment associated with obesity and T2DM during aging.