Targeting the TNFα/TNFR1 axis alleviates the experimental acute pancreatitis

Objective : Acute pancreatitis (AP) is an inflammatory disorder of the pancreas that can lead to life-threatening systemic inflammation and multiple organ failure with high mortality. The binding of tumor necrosis factor α (TNFα) to its receptor TNFR1 is a key driver of inflammation. Here, we demonstrate that genetic ablation or pharmacological inhibition of TNFR1 alleviate AP through reprogramming the immune microenvironment. Methods : Experimental AP models were established in both Wild-type (WT) and Tnfr1 ^-/- mice using three distinct methods for cross validation: cerulein administration, pancreatic duct ligation (PDL), and L-arginine injection. The TNF/TNFR1 axis was pharmacologically inhibited by Pomalidomide, Infliximab and Necrostatin-1 to evaluate their therapeutic effects in AP. Single-cell RNA (scRNA) and bulk RNA sequencing were employed to investigate the underlying mechanisms. Results : We found the hyperactivation of the TNF/TNFR1 axis in AP models by analyzing publicly available scRNA-seq dataset. TNFα and TNFR1 mRNA and protein levels were significantly upregulated across three distinct AP animal models. Notably, genetic ablation of Tnfr1 in mice obviously diminished AP severity, characterized by reduced inflammatory cell infiltration and decreased tissue inflammation. ScRNA-seq analysis revealed an altered immune landscape in Tnfr1 ^-/- mice, featuring both deceased proportions of inflammatory cells and the emergence of unique inflammatory suppression myeloid and neutrophil subpopulations. Furthermore, Integrated 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. Conclusions : This study demonstrates that TNFα/TNFR1 axis drives AP pathogenesis, with Tnfr1 ablation significantly reducing inflammation. We identify pomalidomide as a novel therapeutic agent that effectively attenuates AP severity by inhibiting this pathway, offering promising clinical translation potential.