Old drugs with new applications: Tofacitinib-mediated inhibition of M1-like macrophage polarization in acute pancreatitis by the JAK/STAT and emerging NOD-like receptor pathways.

BACKGROUND

Given the potential for persistent inflammation to induce severe systemic inflammatory consequences, the development of new drugs for the early inflammatory cascade of acute pancreatitis (AP) is particularly important. The aim of this study was to investigate the activity of the JAK inhibitor tofacitinib (TOFA) against AP.

METHODS

In vivo, TOFA efficacy against AP was assessed in a mouse model induced by the intraperitoneal injection of caerulein and retrograde pancreatic duct infusion of sodium taurocholate (STC). In vitro, we evaluated the effect of TOFA on the polarization of mouse macrophages (RAW264.7) exposed to lipopolysaccharide (LPS) alone or in combination with IFN-γ. In addition, to verify that TOFA improves AP via JAK/STAT inhibition, RNA-Seq was used to explore potential signalling cascades that inhibit M1 polarization.

RESULTS

TOFA significantly improved pancreatic injury and the inflammatory response in two AP mouse models by inhibiting M1 macrophage polarization in vivo and in vitro. The inhibitory effects of TOFA were mediated by JAK/STAT pathway suppression (reducing p-STAT1 and p-STAT3). Furthermore, after the administration of filgotinib (a JAK1 inhibitor), TOFA still significantly inhibited macrophage M1 polarization. RNA-Seq, qPCR and Western blotting subsequently confirmed that TOFA also has inhibitory effects on the emerging NOD-like receptor signalling pathway. This is primarily reflected in the inhibition of GBP2, GBP5, NLRP3, GSDMD-N and CASP 1 protein expression.

CONCLUSIONS

TOFA improves macrophage M1 polarization and the associated inflammatory storm stimulated by AP by inhibiting the primary JAK/STAT pathway and the emerging NOD-like receptor pathway. This study expands the new use of the old drug TOFA in the clinical treatment of AP.