CCR2 knockout exacerbates cerulein-induced chronic pancreatitis with hyperglycemia via decreased GLP-1 receptor expression and insulin secretion

Yuji Nakamura, Takanori Kanai, Keita Saeki, Miho Takabe, Junichiro Irie, Jun Miyoshi, Yohei Mikami, Toshiaki Teratani, Takahiro Suzuki, Naoteru Miyata, Tadakazu Hisamatsu, Nobuhiro Nakamoto, Yoshiyuki Yamagishi, Hajime Higuchi, Hirotoshi Ebinuma, Shigenari Hozawa, Hidetsugu Saito, Hiroshi Itoh, Toshifumi Hibi

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Glucagonlike peptide-1 (GLP-1) promotes insulin release; however, the relationship between the GLP-1 signal and chronic pancreatitis is not well understood. Here we focus on chemokine (C-C motif) ligand 2 (CCL2) and its receptor (CCR2) axis, which regulates various immune cells, including macrophages, to clarify the mechanism of GLP-1-mediated insulin secretion in chronic pancreatitis in mice. One and multiple series of repetitive cerulein administrations were used to induce acute and chronic cerulein pancreatitis, respectively. Acute cerulein-administered CCR2-knockout (KO) mice showed suppressed infiltration of CD11b+Gr-1low macrophages and pancreatic inflammation and significantly upregulated insulin secretion compared with paired wild-type (WT) mice. However, chronic cerulein-administered CCR2-KO mice showed significantly increased infiltration of CD11b+/ Gr-1 -and CD11b+/Gr-1high cells, but not CD11b+/Gr-1low cells, in pancreas with severe inflammation and significantly decreased insulin secretion compared with their WT counterparts. Furthermore, although serum GLP-1 levels in chronic cerulein-administered WT and CCR2-KO mice were comparably upregulated after cerulein administrations, GLP-1 receptor levels in pancreases of chronic ceruleinadministered CCR2-KO mice were significantly lower than in paired WT mice. Nevertheless, a significantly higher hyperglycemia level in chronic cerulein-administered CCR2-KO mice was markedly restored by treatment with a GLP-1 analog to a level comparable to the paired WT mice. Collectively, the CCR2/CCL2 axis-mediated CD11b+-cell migration to the pancreas is critically involved in chronic pancreatitismediated hyperglycemia through the modulation of GLP-1 receptor expression and insulin secretion.

Original languageEnglish
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume304
Issue number8
DOIs
Publication statusPublished - 2013

Fingerprint

Ceruletide
Peptide Receptors
Chronic Pancreatitis
Hyperglycemia
Insulin
Knockout Mice
Pancreas
Peptides
CCR2 Receptors
Macrophages
Inflammation
Chemokine CCL2
Protein Sorting Signals
Cell Movement
Ligands
Serum

Keywords

  • Cerulein
  • Glucose tolerance
  • Islet cell
  • Macrophage
  • Pancreatitis

ASJC Scopus subject areas

  • Gastroenterology
  • Physiology (medical)
  • Physiology
  • Hepatology

Cite this

CCR2 knockout exacerbates cerulein-induced chronic pancreatitis with hyperglycemia via decreased GLP-1 receptor expression and insulin secretion. / Nakamura, Yuji; Kanai, Takanori; Saeki, Keita; Takabe, Miho; Irie, Junichiro; Miyoshi, Jun; Mikami, Yohei; Teratani, Toshiaki; Suzuki, Takahiro; Miyata, Naoteru; Hisamatsu, Tadakazu; Nakamoto, Nobuhiro; Yamagishi, Yoshiyuki; Higuchi, Hajime; Ebinuma, Hirotoshi; Hozawa, Shigenari; Saito, Hidetsugu; Itoh, Hiroshi; Hibi, Toshifumi.

In: American Journal of Physiology - Gastrointestinal and Liver Physiology, Vol. 304, No. 8, 2013.

Research output: Contribution to journalArticle

Nakamura, Yuji ; Kanai, Takanori ; Saeki, Keita ; Takabe, Miho ; Irie, Junichiro ; Miyoshi, Jun ; Mikami, Yohei ; Teratani, Toshiaki ; Suzuki, Takahiro ; Miyata, Naoteru ; Hisamatsu, Tadakazu ; Nakamoto, Nobuhiro ; Yamagishi, Yoshiyuki ; Higuchi, Hajime ; Ebinuma, Hirotoshi ; Hozawa, Shigenari ; Saito, Hidetsugu ; Itoh, Hiroshi ; Hibi, Toshifumi. / CCR2 knockout exacerbates cerulein-induced chronic pancreatitis with hyperglycemia via decreased GLP-1 receptor expression and insulin secretion. In: American Journal of Physiology - Gastrointestinal and Liver Physiology. 2013 ; Vol. 304, No. 8.
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abstract = "Glucagonlike peptide-1 (GLP-1) promotes insulin release; however, the relationship between the GLP-1 signal and chronic pancreatitis is not well understood. Here we focus on chemokine (C-C motif) ligand 2 (CCL2) and its receptor (CCR2) axis, which regulates various immune cells, including macrophages, to clarify the mechanism of GLP-1-mediated insulin secretion in chronic pancreatitis in mice. One and multiple series of repetitive cerulein administrations were used to induce acute and chronic cerulein pancreatitis, respectively. Acute cerulein-administered CCR2-knockout (KO) mice showed suppressed infiltration of CD11b+Gr-1low macrophages and pancreatic inflammation and significantly upregulated insulin secretion compared with paired wild-type (WT) mice. However, chronic cerulein-administered CCR2-KO mice showed significantly increased infiltration of CD11b+/ Gr-1 -and CD11b+/Gr-1high cells, but not CD11b+/Gr-1low cells, in pancreas with severe inflammation and significantly decreased insulin secretion compared with their WT counterparts. Furthermore, although serum GLP-1 levels in chronic cerulein-administered WT and CCR2-KO mice were comparably upregulated after cerulein administrations, GLP-1 receptor levels in pancreases of chronic ceruleinadministered CCR2-KO mice were significantly lower than in paired WT mice. Nevertheless, a significantly higher hyperglycemia level in chronic cerulein-administered CCR2-KO mice was markedly restored by treatment with a GLP-1 analog to a level comparable to the paired WT mice. Collectively, the CCR2/CCL2 axis-mediated CD11b+-cell migration to the pancreas is critically involved in chronic pancreatitismediated hyperglycemia through the modulation of GLP-1 receptor expression and insulin secretion.",
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AU - Takabe, Miho

AU - Irie, Junichiro

AU - Miyoshi, Jun

AU - Mikami, Yohei

AU - Teratani, Toshiaki

AU - Suzuki, Takahiro

AU - Miyata, Naoteru

AU - Hisamatsu, Tadakazu

AU - Nakamoto, Nobuhiro

AU - Yamagishi, Yoshiyuki

AU - Higuchi, Hajime

AU - Ebinuma, Hirotoshi

AU - Hozawa, Shigenari

AU - Saito, Hidetsugu

AU - Itoh, Hiroshi

AU - Hibi, Toshifumi

PY - 2013

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N2 - Glucagonlike peptide-1 (GLP-1) promotes insulin release; however, the relationship between the GLP-1 signal and chronic pancreatitis is not well understood. Here we focus on chemokine (C-C motif) ligand 2 (CCL2) and its receptor (CCR2) axis, which regulates various immune cells, including macrophages, to clarify the mechanism of GLP-1-mediated insulin secretion in chronic pancreatitis in mice. One and multiple series of repetitive cerulein administrations were used to induce acute and chronic cerulein pancreatitis, respectively. Acute cerulein-administered CCR2-knockout (KO) mice showed suppressed infiltration of CD11b+Gr-1low macrophages and pancreatic inflammation and significantly upregulated insulin secretion compared with paired wild-type (WT) mice. However, chronic cerulein-administered CCR2-KO mice showed significantly increased infiltration of CD11b+/ Gr-1 -and CD11b+/Gr-1high cells, but not CD11b+/Gr-1low cells, in pancreas with severe inflammation and significantly decreased insulin secretion compared with their WT counterparts. Furthermore, although serum GLP-1 levels in chronic cerulein-administered WT and CCR2-KO mice were comparably upregulated after cerulein administrations, GLP-1 receptor levels in pancreases of chronic ceruleinadministered CCR2-KO mice were significantly lower than in paired WT mice. Nevertheless, a significantly higher hyperglycemia level in chronic cerulein-administered CCR2-KO mice was markedly restored by treatment with a GLP-1 analog to a level comparable to the paired WT mice. Collectively, the CCR2/CCL2 axis-mediated CD11b+-cell migration to the pancreas is critically involved in chronic pancreatitismediated hyperglycemia through the modulation of GLP-1 receptor expression and insulin secretion.

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KW - Macrophage

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