Targeting the TNFα/TNFR1 axis to alleviate inflammation in experimental acute pancreatitis

Acute pancreatitis (AP) is an inflammatory disorder of the pancreas that can progress to systemic inflammatory response syndrome and multiple organ failure with high mortality. TNFα (tumor necrosis factor-alpha), a key proinflammatory cytokine elevated in early AP, triggers both pancreatic inflammation and acinar cell apoptosis through TNFR1 (tumor necrosis factor-alpha receptor 1) binding. Our study first revealed significant upregulation of TNFα and TNFR1 across three distinct AP animal models. Genetic ablation of Tnfr1 resulted in markedly attenuated AP severity in Tnfr1-/- mice, characterized by reduced inflammatory cell infiltration and decreased tissue inflammation. In bulk RNA analysis identified downregulation of interferon-related genes (Ifi209, Marcksl1, Ifit3, Oas3) in inflammatory cells of Tnfr1-/- mice. Pharmacological inhibition of the TNFα/TNFR1 axis using pomalidomide pretreatment similarly attenuated AP inflammation and significantly suppressed these interferon-associated genes. Notably, therapeutic administration of pomalidomide post-AP induction reproduced these protective effects, confirming the translational potential of targeting this signaling pathway.