CCL2-induced migration and SOCS3-mediated activation of macrophages are involved in cerulein-induced pancreatitis in mice

Keita Saeki, Takanori Kanai, Masaru Nakano, Yuji Nakamura, Naoteru Miyata, Tomohisa Sujino, Yoshiyuki Yamagishi, Hirotoshi Ebinuma, Hiromasa Takaishi, Yuuichi Ono, Kazuyoshi Takeda, Shigenari Hozawa, Akihiko Yoshimura, Toshifumi Hibi

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Abstract

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-arginineinduced 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 CD11b highCD11c - cells, were detected in the pancreas of healthy mice. However, activated CD11b highCD11c - cells, including Gr-1 low macrophages and Gr-1 high 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 CD11b highCD11c -Gr-1 low 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 CD11b highCD11c -Gr-1 low 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-1 low macrophage produced less tumor necrosis factor-α than wild-type mice given cerulein, although the absolute number of CD11b highCD11c -Gr-1 low 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 CD11b highCD11c -Gr-1 low macrophage from the bone marrow (mediated by CCL2 via CCR2) and suppressor of cytokine signaling 3dependent activation of macrophage. These findings might lead to new therapeutic strategies for acute pancreatitis.

Original languageEnglish
JournalGastroenterology
Volume142
Issue number4
DOIs
Publication statusPublished - 2012 Apr

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Ceruletide
Macrophage Activation
Pancreatitis
Macrophages
Parabiosis
Bone Marrow
Pancreas
CCR2 Receptors
Cytokines
Injections
Acinar Cells
Amylases
Lipase
Granulocytes
Arginine
Leukocytes
Tumor Necrosis Factor-alpha
Hemodynamics
Pathology
Inflammation

Keywords

  • Chemokine
  • Immune Response
  • Mouse Model
  • Signaling

ASJC Scopus subject areas

  • Gastroenterology

Cite this

CCL2-induced migration and SOCS3-mediated activation of macrophages are involved in cerulein-induced pancreatitis in mice. / 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.

In: Gastroenterology, Vol. 142, No. 4, 04.2012.

Research output: Contribution to journalArticle

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. / CCL2-induced migration and SOCS3-mediated activation of macrophages are involved in cerulein-induced pancreatitis in mice. In: Gastroenterology. 2012 ; Vol. 142, No. 4.
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AU - Saeki, Keita

AU - Kanai, Takanori

AU - Nakano, Masaru

AU - Nakamura, Yuji

AU - Miyata, Naoteru

AU - Sujino, Tomohisa

AU - Yamagishi, Yoshiyuki

AU - Ebinuma, Hirotoshi

AU - Takaishi, Hiromasa

AU - Ono, Yuuichi

AU - Takeda, Kazuyoshi

AU - Hozawa, Shigenari

AU - Yoshimura, Akihiko

AU - Hibi, Toshifumi

PY - 2012/4

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N2 - 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-arginineinduced 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 CD11b highCD11c - cells, were detected in the pancreas of healthy mice. However, activated CD11b highCD11c - cells, including Gr-1 low macrophages and Gr-1 high 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 CD11b highCD11c -Gr-1 low 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 CD11b highCD11c -Gr-1 low 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-1 low macrophage produced less tumor necrosis factor-α than wild-type mice given cerulein, although the absolute number of CD11b highCD11c -Gr-1 low 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 CD11b highCD11c -Gr-1 low macrophage from the bone marrow (mediated by CCL2 via CCR2) and suppressor of cytokine signaling 3dependent activation of macrophage. These findings might lead to new therapeutic strategies for acute pancreatitis.

AB - 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-arginineinduced 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 CD11b highCD11c - cells, were detected in the pancreas of healthy mice. However, activated CD11b highCD11c - cells, including Gr-1 low macrophages and Gr-1 high 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 CD11b highCD11c -Gr-1 low 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 CD11b highCD11c -Gr-1 low 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-1 low macrophage produced less tumor necrosis factor-α than wild-type mice given cerulein, although the absolute number of CD11b highCD11c -Gr-1 low 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 CD11b highCD11c -Gr-1 low macrophage from the bone marrow (mediated by CCL2 via CCR2) and suppressor of cytokine signaling 3dependent activation of macrophage. These findings might lead to new therapeutic strategies for acute pancreatitis.

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KW - Immune Response

KW - Mouse Model

KW - Signaling

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