Trem2+ macrophages alleviate renal tubule lipid accumulation and ferroptosis in Diabetic Nephropathy by repressing IL-1β-mediated CD36 expression

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 in myeloid cells 2 (Trem2) in kidneys of DN patients and mouse. Here, we intend to explore the characteristics and the function of Trem2+ macrophages in the progress of DN. RNA-Seq of macrophages in kidneys of Trem2 KO (Knockout) mice with High fat diet plus Streptozotocin (HFD/STZ) treatment revealed functional enrichment of metabolic processes, cytokine production, positive regulation of 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 ERK signaling pathway. Furthermore, IL-1β triggers CD36 expression via the transcription factor NF-κB. Bioinformatics and functional assays show 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, Trem2 plays a role in enhancing the phagocytosis and clearance of ferroptotic cells by BMDMs. Altogether, our results suggest that Trem2⁺macrophages maintain homeostasis of the renal microenvironment and exerted protective function in DN.