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Trem2+ Macrophages Alleviate Renal Tubule Lipid Accumulation and Ferroptosis in Diabetic Nephropathy by Repressing
Xue Wang1, Jiayi Wan1,2, Chao Wang1
1Department of Nephrology, First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Medical Devices and Integrated Traditional Chinese and Western Drug Development for Severe Kidney Diseases, Beijing Key Laboratory of Digital Intelligent TCM for the Prevention and Treatment of Pan-vascular Diseases, Key Disciplines of National Administration of Traditional Chinese Medicine (zyyzdxk-2023310), Beijing, China.
Abstract:
The presence of macrophages surrounding lipotoxic tubular epithelial cells (TECs) is a hallmark of diabetic nephropathy (DN). Nevertheless, the mechanisms of communication between these cell types are not well understood. Previous studies have revealed a unique subset of macrophages that express triggering receptor expressed on myeloid cells 2 (Trem2) in kidneys of human patients and mice with DN. Here, we explored the characteristics and the function of Trem2+ macrophages in the progress of DN. RNA-sequencing of macrophages in kidneys of Trem2 knockout (KO) mice fed a high-fat diet plus streptozotocin (HFD/STZ) revealed functional enrichment of metabolic processes, cytokine production, positive regulation of extracellular signal-regulated kinase (ERK) cascades, and the regulation of phagocytosis. In vivo studies demonstrated that Trem2+ macrophages reduced lipid accumulation and mitigated ferroptosis of TECs in diabetic mice. Mechanistically, Trem2-deficient macrophages amplified the production of interleukin-1β (IL-1β) through activating the ERK signaling pathway. Furthermore, IL-1β triggered CD36 expression via the transcription factor NF-κB. Bioinformatics and functional assays showed NF-κB binds the CD36 promoter, which directly bound to the promoters of CD36 to facilitate its transcription. Inhibition of NF-κB blocked IL-1β-induced CD36 production. This mechanism is exacerbated in Trem2-deficient macrophages, which release excess IL-1β to activate NF-κB in tubular cells, promoting CD36-dependent lipid uptake and ferroptosis. Additionally, we found Trem2 plays a role in enhancing the phagocytosis and clearance of ferroptotic cells by bone marrow-derived macrophages. Altogether, our results suggest Trem2+ macrophages maintain homeostasis of the renal microenvironment and exert a protective function in DN.
Article Highlights:
Levels of triggering receptor expressed on myeloid cells 2 (Trem2) in macrophages are increased in human patients and in mice with diabetic nephropathy. Trem2 suppresses the extracellular signal-regulated kinase signaling pathways, thereby inhibiting IL-1β production in macrophages. Macrophage Trem2 deficiency exacerbates tubular cell lipid deposition and ferroptosis by increasing CD36 expression in an IL-1β-dependent manner.
