Toll‐like receptor 3 expression in myeloid cells is essential for efficient regeneration after acute pancreatitis in mice. Issue 5 (22nd March 2021)

• Record Type: Journal Article
• Authors: Hidalgo‐Sastre, Ana; Kuebelsbeck, Ludwig A.; Jochheim, Leonie S.; Staufer, Lina M.; Altmayr, Felicitas; Johannes, Widya; Steiger, Katja; Ronderos, Monica; Hartmann, Daniel; Hüser, Norbert; Schmid, Roland M.; Holzmann, Bernhard; von Figura, Guido
• Is Part Of: European journal of immunology. Volume 51:Issue 5(2021)
• Page Start: 1182
• Page End: 1194
• Publication Date: 2021-03-22
• Subjects: acute pancreatitis -- ADM -- macrophages -- myeloid cells -- TLR3; Immunology -- Periodicals; 616.079
• DOI: 10.1002/eji.202048771
• Languages: English
• ISSNs: 0014-2980

Abstract

Abstract: Stringent regulation of the inflammatory response is crucial for normal tissue regeneration. Here, we analyzed the role of Toll‐like receptor 3 (TLR3) in pancreatic regeneration after acute pancreatitis (AP). AP was induced by caerulein treatment in mice with global TLR3 deficiency (TLR3 OFF ) or in mice re‐expressing TLR3 exclusively in the myeloid cell lineage (TLR3 Mye ). Compared to WT mice, TLR3 OFF mice had a markedly increased formation of acinar‐to‐ductal metaplasia (ADM) that persisted until day 7 after initiation of AP. Pancreatic tissue of WT mice was completely regenerated after 5 days with no detectable ADM structures. The enhancing effect of TLR3‐deficiency on ADM formation was closely linked with an increased and prolonged accumulation of macrophages in pancreata of TLR3 OFF mice. Importantly, the phenotype of TLR3 OFF mice was rescued in TLR3 Mye mice, demonstrating the causative role of myeloid cell selective TLR3 signaling. Moreover, in vitro stimulation of macrophages through TLR3 initiated cell death by a caspase‐8‐associated mechanism. Therefore, these findings provide evidence that TLR3 signaling in myeloid cells is sufficient to limit inflammation and ADM formation and to promote regeneration after AP. Notably, resolution of inflammation after AP was associated with macrophage sensitivity to TLR3‐mediated cell death. Abstract : TLR3‐deficient mice have increased and persistent acinar‐to‐ductal metaplasia after acute pancreatitis combined with an accumulation of pancreatic macrophages. The exclusive expression of TLR3 in myeloid cells rescues this regenerative defect. In vitro, TLR3 signaling induces caspase‐8‐associated cell death of macrophages, which possibly causes the resolution of inflammation.