Frontiers in Immunology · Nov 3, 2026
Macrophage senescence in diabetic kidney disease: an identity gap and a testable, phase-dependent framework
By Xiaomeng Lin, Wenting Li, Changlin Li et al.
Cellular senescence is increasingly invoked to explain premature aging of the diabetic kidney. Kidney macrophages accumulate early in diabetic kidney disease (DKD), drive tubulointerstitial inflammation, and share senescence-inducing stressors with parenchymal cells. Although senescence-associated features have been reported in DKD macrophages, senescent macrophages meeting consensus multi-marker criteria remain unconfirmed in human DKD. This identity gap motivates our review: multi-marker, spatially resolved evidence anchored to lineage identity is needed before macrophage senescence can be accepted as a therapeutic target. We propose that, if macrophage senescence occurs, its functional meaning depends on disease phase. Early senescence programs may be adaptive and reversible. During progression, tubule–macrophage vesicle exchange, early fibrosis-associated macrophage phenotypic switching (including macrophage-to-myofibroblast transition), and divergence between trained immunity and terminal arrest may determine resolution or propagation. In established DKD, senescence-associated secretory phenotype (SASP)–NLRP3 feedback, ferroptosis coupling, and failed immunosurveillance may sustain pathology. This framework implies phase-matched strategies: senomorphics early, biomarker-timed blockade of extracellular-vesicle senescence propagation during progression, and intermittent macrophage-directed senolysis in established disease. It yields three falsifiable predictions: senolytic benefit will invert with phase; biomarker enrichment will amplify treatment responses; and the p21high macrophage subset will be protective early but not late. We grade each mechanistic link by how directly it implicates macrophages and distinguish human DKD evidence from preclinical inference throughout. Testing these predictions will determine whether the framework holds.