Luteolin as a novel therapeutic for diabetic kidney disease: Targeting the ADAM10-TREM2 pathway

Luteolin enhances efferocytosis of TREM2 + Macrophages in diabetic kidney disease via targeting ADAM10. Under physiological conditions, apoptotic renal tubular epithelial cells release “eat-me” molecular signals that are recognized and bound by TREM2 receptors on interstitial TREM2 + macrophages, initiating efferocytosis (the phagocytic clearance of apoptotic cells). This process prevents secondary necrosis and suppresses proinflammatory cytokine upregulation, thereby maintaining immune homeostasis. In diabetic kidney disease (DKD), however, hyperglycemic conditions induce pathological upregulation of ADAM10 activity. This metalloprotease-dependent enhancement accelerates TREM2 ectodomain shedding from macrophage surfaces, reducing full-length TREM2 membrane expression and consequently impairing efferocytic capacity of TREM2 + macrophages. The resulting accumulation of uncleared apoptotic cells triggers proinflammatory cytokine elevation and exacerbates inflammation. Luteolin directly binds to ADAM10, inhibiting its activity. This intervention restores full-length TREM2 expression on the surface of macrophages, enhances efferocytic function, reestablishes immune homeostasis, mitigates DKD-associated inflammatory pathology, and ultimately ameliorates renal dysfunction and structural damage. • Luteolin ameliorates proteinuria, renal dysfunction, pathological injury, and inflammation in the db / db mice. • Luteolin targets and directly binds to ADAM10—the protease responsible for TREM2 cleavage—and inhibits its activity. • Luteolin inhibits the cleavage of full-length TREM2 protein on macrophage membranes, thereby maintaining the abundance of TREM2 + macrophages. • Luteolin enhances the efferocytosis (clearance of apoptotic cells) of apoptotic renal tubular epithelial cells by TREM2 + macrophages both in vitro and in vivo , consequently suppressing immune inflammation. Diabetic kidney disease (DKD) is a common condition with few treatment options, and inflammation plays a pivotal role in its progression. Luteolin, a natural compound found in traditional Chinese herbs, is known for its anti-inflammatory properties, making it a potential treatment for DKD. But its effect and mechanisms in DKD remain incompletely elucidated. Renoprotective effects of luteolin in db / db mice were assessed with BUN, Scr, uACR, and PAS staining. Flow cytometry and extraction of total membrane proteins were conducted to examine the abundance of full-length TREM2 on the membrane of macrophages. Co-culture of differentially treated macrophages and HK2 cells evaluated luteolin’s impact on efferocytosis. The molecular target of luteolin was elucidated through virtual molecular analysis, SPR, and ADAM10 activity assays. Luteolin reduced uACR, BUN, and SCr levels. Histologic analyses showed decreases in mesangial matrix, glomerular volume, GBM thickness, and foot process effacement. Tubular injury scores and KIM1 expression were lowered, while megalin and cubilin expression increased. Renal macrophage infiltration, iNOS + cells, and IL-1β, IL-18, TNF-α, and MCP-1 levels were reduced. Luteolin elevated TREM2 + macrophages with decreased sTREM2 in vivo and in vitro . Immunofluorescence confirmed increased TREM2 + macrophages and enhanced full-length TREM2 on cell membrane. Luteolin exhibited dose-dependent binding to ADAM10 and inhibited its activity without affecting ADAM10 expression. In co-culture system, luteolin increased p-DAP12, p-SYK, and PHrodo + cell counts. Apoptotic cells in kidney tissue decreased, while Rab5a and Rab7a expression were upregulated. Luteolin attenuates immunoinflammation and pathological injury in db / db mice by enhancing the efferocytosis of apoptotic renal tubular cells by TREM2 + macrophages. The potential mechanism of luteolin involves binding to ADAM10 and inhibiting its activity, which attenuates aberrant shedding of full-length TREM2 from macrophages and potentiates downstream TREM2 signaling. Collectively, luteolin provides a promising option for ameliorating immune inflammation in DKD, demonstrating strong translational potential.