CCL2-Induced Migration and SOCS3-Mediated Activation of Macrophages Are Involved in Cerulein-Induced Pancreatitis in Mice

• Published in: Gastroenterology (New York, N.Y. 1943) Vol. 142; no. 4; pp. 1010 - 1020.e9
• Main Authors: Saeki, Keita, Kanai, Takanori, Nakano, Masaru, Nakamura, Yuji, Miyata, Naoteru, Sujino, Tomohisa, Yamagishi, Yoshiyuki, Ebinuma, Hirotoshi, Takaishi, Hiromasa, Ono, Yuuichi, Takeda, Kazuyoshi, Hozawa, Shigenari, Yoshimura, Akihiko, Hibi, Toshifumi
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.04.2012
• Subjects: Acute Disease; Animals; Arginine; Biomarkers - metabolism; CD11b Antigen - metabolism; CD11c Antigen - metabolism; Ceruletide; Chemokine; Chemokine CCL2 - deficiency; Chemokine CCL2 - genetics; Chemokine CCL2 - metabolism; Chemotaxis; Disease Models, Animal; DNA-Binding Proteins - deficiency; DNA-Binding Proteins - genetics; Enzymes - blood; Gastroenterology and Hepatology; Immune Response; Immunity, Innate; Lymphocyte Depletion; Macrophage Activation; Macrophages - immunology; Macrophages - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Mouse Model; Pancreas - immunology; Pancreas - metabolism; Pancreas - pathology; Pancreas - surgery; Pancreatitis - chemically induced; Pancreatitis - immunology; Pancreatitis - metabolism; Pancreatitis - pathology; Pancreatitis - prevention & control; Parabiosis; Receptors, CCR2 - metabolism; Receptors, Chemokine - metabolism; Signal Transduction; Signaling; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins - metabolism; TCR; MDSC; antigen-presenting cell; cKO; nuclear factor−κB; BM; phosphate-buffered saline; L-arginine; LPS; T-cell receptor; NF-κB; natural killer; myeloid-derived suppressor cell; interleukin; WT; Mouse Model; PBS; natural killer T cell; recombinase-activated gene-2; suppressor of cytokine signaling; cDC; IL; Immune Response; signal transducer and activation of transcription; SOCS; bone marrow; Chemokine; Signaling; L-Arg; STAT; classical dendritic cells; APC; TNF-α; tumor necrosis factor−α; NKT; conditional knockout; lipopolysaccharide; wild-type; NK; RAG-2
• ISSN: 0016-5085; 1528-0012
• DOI: 10.1053/j.gastro.2011.12.054

Background & Aims Acute pancreatitis is a common inflammatory disease mediated by damage to acinar cells and subsequent pancreatic inflammation with recruitment of leukocytes. We investigated the pathologic roles of innate immune cells, especially macrophages, in cerulein– and L-arginine–induced acute pancreatitis in mice. Methods Acute pancreatitis was induced by sequential peritoneal administration of cerulein to mice. We determined serum concentrations of amylase and lipase, pancreatic pathology, and features of infiltrating mononuclear cells. We performed parabiosis surgery to assess the hemodynamics of pancreatic macrophages. Results Almost all types of immune cells, except for CD11bhigh CD11c− cells, were detected in the pancreas of healthy mice. However, activated CD11bhigh CD11c− cells, including Gr-1low macrophages and Gr-1high cells (granulocytes and myeloid-derived suppressor cells), were detected in damaged pancreas after cerulein administration. CCL2−/− mice given cerulein injections developed significantly less severe pancreatitis, with less infiltration of CD11bhigh CD11c− Gr-1low macrophages, but comparable infiltration of myeloid-derived suppressor cells, compared with cerulein-injected wild-type mice. Parabiosis and bone marrow analyses of these mice revealed that the CD11bhigh CD11c− Gr-1low macrophages had moved out of the bone marrow. Furthermore, mice with macrophage-specific deletion of suppressor of cytokine signaling 3 given injections of cerulein developed less severe pancreatitis and Gr-1low macrophage produced less tumor necrosis factor-α than wild-type mice given cerulein, although the absolute number of CD11bhigh CD11c− Gr-1low macrophages was comparable between strains. Induction of acute pancreatitis by L-arginine required induction of macrophage migration by CCL2, via the receptor CCR2. Conclusions Cerulein induction of pancreatitis in mice involves migration of CD11bhigh CD11c− Gr-1low macrophage from the bone marrow (mediated by CCL2 via CCR2) and suppressor of cytokine signaling 3–dependent activation of macrophage. These findings might lead to new therapeutic strategies for acute pancreatitis.