Interleukin-37 overexpression enhances the therapeutic efficacy of adipose-derived mesenchymal stem cells in atopic dermatitis by activating autophagy and improving skin barrier dysfunction.

Adipose-derived mesenchymal stem cells (ADSCs) have emerged as a promising therapeutic option because of their immunomodulatory and tissue-repair capabilities in the treatment of Atopic dermatitis (AD). However, their efficacy is limited by cellular senescence and functional decline. Interleukin-37 (IL-37), an anti-inflammatory cytokine, has shown potential in mitigating inflammation and enhancing skin barrier function. This study investigated whether IL-37 overexpression in ADSCs could augment their therapeutic effects in AD and the underlying mechanism. Lentiviral-mediated IL-37 overexpression in ADSCs enhanced proliferation, reduced senescence (evidenced by decreased β-galactosidase activity), and activated autophagy, as shown by elevated LC3B-II/I and Beclin-1 levels, reduced p62, and increased LC3B puncta formation. These effects were reversed by the autophagy inhibitor 3-MA. In an IL-4/IL-13-induced HaCaT cell model of AD, coculture with IL-37-overexpressing ADSCs promoted keratinocyte proliferation, reduced apoptosis, suppressed proinflammatory cytokines (IL-1β, IL-6, tumor necrosis factor-α, thymus and activation-regulated chemokine), and restored the expression of skin barrier proteins (Filaggrin, Involucrin). In vivo, local injection of IL-37-overexpressing ADSCs into lesional skin in a 2,4-dinitrochlorobenzene-induced AD mouse model attenuated skin lesions, reduced inflammation, and improved barrier protein expression. These results demonstrate that IL-37 overexpression enhances the therapeutic efficacy of ADSCs in AD through autophagy activation and restoration of skin barrier function, providing a novel genetically engineered stem cell-based strategy for the treatment of AD. SIGNIFICANCE STATEMENT: IL-37-engineered adipose-derived mesenchymal stem cells improve atopic dermatitis treatment by activating autophagy to reduce senescence and enhance proliferation. These cells suppress inflammation while restoring skin barrier proteins, providing a novel therapy for refractory skin diseases.