SphK1/S1P signaling-mediated crosstalk between pancreatic acinar cell and macrophage M1 polarization aggravates acute pancreatitis progression.

Studies have shown that M1 polarization of macrophages plays a crucial role in pathogenesis of acute pancreatitis (AP), although the underlying mechanisms remain incompletely understood. In this study, an in vivo AP model was induced in mice using caerulein or L-arginine, while an in vitro AP model was established by treating pancreatic acinar cells (PACs) with cholecystokinin (CCK). We observed a significant upregulation of SphK1/S1P in both CCK-treated PACs and the pancreatic tissue of AP mice. In contrast, inflammation and M1 macrophage polarization were markedly attenuated in SphK1(-/-) AP mice and upon treatment with pharmacological inhibitors targeting SphK1 or S1PR2. Similarly, M1 polarization of macrophages was notably induced by injured pancreatic acinar cells (iPACs), but this effect was suppressed by SphK1 knockdown or inhibition. Mechanistically, S1P derived from iPACs specifically bound to S1PR2 on macrophages, activating PI3K/JNK and ERK pathways to induce M1 polarization. Moreover, TNF-α secreted by M1 macrophages enhanced SphK1 transcription in PACs through NF-κB activation, forming a positive feedback loop between iPACs and macrophage M1 polarization. Collectively, our findings reveal that the SphK1/S1P/S1PR2/TNF-α axis mediates a reciprocal interaction between iPACs and M1 macrophages, which significantly contributes to AP pathogenesis.