Chemokine CXCL16 mediates acinar cell necrosis in cerulein induced acute pancreatitis in mice.

Abstract

Severe acute pancreatitis is a lethal inflammatory disease frequently accompanied by pancreatic necrosis. We aimed to identify a key regulator in the development of pancreatic necrosis. A cytokine/chemokine array using sera from patients with acute pancreatitis (AP) revealed that serum CXCL16 levels were elevated according to the severity of pancreatitis. In a mouse model of AP, Cxcl16 expression was induced in pancreatic acini in the late phase with the development of pancreatic necrosis. Cxcl16-/- mice revealed similar sensitivity as wild-type (WT) mice to the onset of pancreatitis, but better resisted development of acinar cell necrosis with attenuated neutrophil infiltration. A cytokine array and immunohistochemistry revealed lower expression of Ccl9, a neutrophil chemoattractant, in the pancreatic acini of Cxcl16-/- mice than WT mice. Ccl9 mRNA expression was induced by stimulation with Cxcl16 protein in pancreatic acinar cells in vitro, suggesting a Cxcl16/Ccl9 cascade. Neutralizing antibody against Cxcl16 ameliorated pancreatic injury in the mouse AP model with decreased Ccl9 expression and less neutrophil accumulation. In conclusion, Cxcl16 expressed in pancreatic acini contributes to the development of acinar cell necrosis through the induction of Ccl9 and subsequent neutrophil infiltration. CXCL16 could be a new therapeutic target in AP.

• Authors: Yojiro Sakuma, Yuzo Kodama, Takaaki Eguchi, Norimitsu Uza, Yoshihisa Tsuji, Masahiro Shiokawa, Takahisa Maruno, Katsutoshi Kuriyama, Yoshihiro Nishikawa, Yuki Yamauchi, Motoyuki Tsuda, Tatsuki Ueda, Tomoaki Matsumori, Toshihiro Morita, Teruko Tomono, Nobuyuki Kakiuchi, Atsushi Mima, Yuko Sogabe, Saiko Marui, Takeshi Kuwada, Akihiko Okada, Tomohiro Watanabe, Hiroshi Nakase, Tsutomu Chiba, Hiroshi Seno
• Journal: Scientific reports (Sci Rep) Vol. 8 Issue 1 Pg. 8829 (06 11 2018) ISSN: 2045-2322 [Electronic] England
• PMID: 29891873 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CXCL16 protein, human
• Ccl9 protein, mouse
• Chemokine CXCL16
• Chemokines, CC
• Cxcl16 protein, mouse
• Macrophage Inflammatory Proteins
• Ceruletide

Topics

• Acinar Cells (metabolism, pathology)
• Animals
• Ceruletide (administration & dosage, toxicity)
• Chemokine CXCL16 (blood, deficiency, metabolism)
• Chemokines, CC (analysis, blood)
• Disease Models, Animal
• Humans
• Immunohistochemistry
• Macrophage Inflammatory Proteins (analysis, blood)
• Mice
• Mice, Knockout
• Neutrophils (immunology)
• Pancreatitis, Acute Necrotizing (chemically induced, pathology)
• Serum (chemistry)