Targeting the NF-κB/Atg5 axis alleviates antibody-mediated rejection by preserving Atg5-dependent Treg regulation and limiting macrophage inflammation

Antibody-mediated rejection (AMR) remains a leading cause of kidney allograft failure, yet the mechanisms linking Treg dysfunction to persistent innate immune activation remain poorly defined. Here, we reveal Atg5-dependent Treg regulation as a key link between Treg dysfunction and macrophage-associated inflammation during AMR. We demonstrate that AMR is characterized by reduced Treg abundance and increased accumulation of pro-inflammatory M1-like macrophages, changes that are attenuated by adoptive transfer of induced Tregs. Mechanistically, Atg5-dependent regulation is required for maintaining Treg-mediated immune control, and loss of Atg5 is associated with impaired autophagy-related signaling and enhanced macrophage inflammatory responses. Importantly, we identify TNF-α/NF-κB signaling as a potential upstream mechanism linking macrophage-associated inflammation to altered Atg5-dependent regulation in Tregs. TNF-α activates NF-κB signaling in Tregs, promotes p65 enrichment at the Atg5 promoter, and is associated with reduced Atg5 expression and alterations in autophagy-associated markers. These effects are largely reversed by NF-κB inhibition, supporting a potential reciprocal interaction between macrophage-associated inflammatory signaling and impaired Treg regulation during AMR. These findings identify Atg5-dependent Treg regulation as a mechanistic link between adaptive immune dysfunction and macrophage-associated inflammation and suggest that preserving Treg autophagy-related function may represent a potential therapeutic strategy for AMR.