Mechanistic insights into TLR2-mediated acute pancreatitis exacerbation via macrophage-ferroptotic acinar cell crosstalk.

Abstract

Ferroptosis is closely linked to increased inflammatory responses and plays a vital role in the development of acute pancreatitis. We investigated how this process contributes to pancreatic injury in AP and examined the interactions between ferroptotic acinar cells and macrophages. Our study profiles the crosstalk mechanisms between ferroptotic acinar cells and macrophages. These findings, derived from human peripheral blood cohorts, were validated in vivo and in vitro. Multi-omics analyses revealed a reduction in pancreatic acinar cells owing to abnormal ferroptosis activation, as confirmed in a cerulein-induced mouse model. Moreover, pretreatment with the ferroptosis inhibitor Lip-1 alleviated acinar cell damage and immune cell infiltration. Results of single-cell RNA analysis indicated that macrophages accumulated near the sites of acinar cell death. Inhibiting ferroptosis significantly decreased macrophage infiltration and M1-like polarization during AP. Mechanistic studies identified Tlr2 as a key gene involved in AP that mediates the interactions between acinar cells and macrophages, promoting inflammation. Tlr2, a receptor for damage-associated molecular patterns linked to AP, was specifically expressed in monocytes/macrophages but not in acinar cells. Genetic knockdown and knockout inhibition did not increase the resistance of acinar cells to ferroptosis in vivo or in vitro. However, inhibiting Tlr2 in macrophages impaired their ability to detect HMGB1 (high mobility group box 1), decreased the stimulation of the NF-κB/NLRP3-signaling pathways, and prevented macrophage polarization to the proinflammatory M1 phenotype. Our results emphasize the role of Tlr2 in the interaction between ferroptotic acinar cells and macrophages, indicating its potential as a therapeutic agent in managing AP.