Augmenting the Endogenous RBM3 Response Protects Against Burn-Induced Acute Kidney Injury by Enhancing Macrophage-Mediated Resolution of Inflammation.

The regulatory mechanisms underlying M1/M2 macrophage polarization and efferocytosis in acute kidney injury (AKI) remain poorly understood. This study aimed to investigate the mechanism by which RBM3 modulates macrophage function to alleviate burn-induced AKI. A standardized scald burn model was established in rats by dorsal immersion in 100°C water for 15 s. Renal function and histopathology were evaluated at 24, 48, and 72 h post-injury through serum biochemistry and hematoxylin and eosin (H&E) staining. RBM3 expression was analyzed by qRT-PCR, Western blot, immunohistochemistry, and flow cytometry. Adenoviral RBM3 was administered to AKI rats, followed by a comprehensive assessment including renal function tests, H&E/TUNEL staining, KIM-1 immunofluorescence, macrophage polarization analysis (M1/M2 markers), and cytokine profiling (IL-6, IL-1β, and TNF-α). Single-cell RNA sequencing identified differentially expressed genes, particularly Slfn4, validated via in vitro knockdown and dual RBM3/Slfn4 interference experiments in bone marrow-derived macrophages to assess polarization and efferocytosis. Peak AKI severity occurred at 48 h post-burn, coinciding with dynamic RBM3 expression. RBM3 overexpression significantly improved renal function, attenuated tissue damage, reduced inflammation as evidenced by decreased levels of IL-6, IL-1β, and TNF-α, promoted M2 polarization characterized by increased Arg1 expression and decreased CD86 and iNOS levels, and enhanced efferocytosis. Slfn4 knockdown replicated the protective effects of RBM3, while RBM3 inhibition exacerbated M1 polarization, effects that were rescued by concurrent Slfn4 suppression. RBM3 ameliorates burn-induced AKI by downregulating Slfn4 to drive a pro-resolving macrophage program. The RBM3-Slfn4 axis may represent a potential therapeutic target for AKI management.