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

Saeki, Kimiko; Kanai, Takanori; Nakano, Masaru; Nakamura, Yuji; Miyata, Naoteru; Sujino, Tomohisa; Yamagishi, Yuka; Ebinuma, Hirotoshi; Takaishi, Hiromasa; Ono, Yoshiki; Takeda, Kazuyoshi; Hozawa, Shigenari; Yoshimura, Akihiko; Hibi, Toshifumi

doi:10.1053/j.gastro.2011.12.054

Cited by 79 publications

(70 citation statements)

References 36 publications

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“…Gordon et al reported that SOCS3 siRNA-mediated gene silencing in M1-activated human monocyte-derived macrophages decreased the expression of proinflammatory factors [42]. Saeki et al reported that cerulein-induced pancreatitis in mice involved the migration of CD11b high CD11c -Gr-1 low monocytes mediated by CCL2-CCR2 and SOCS3-dependent macrophage activation [33]. However, a direct association between SOCS3 signaling and CCL2 secretion has not been established.…”

Section: Discussionmentioning

confidence: 99%

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The Spleen Promotes the Secretion of CCL2 and Supports an M1 Dominant Phenotype in Hepatic Macrophages During Liver Fibrosis

Wei

et al. 2018

Cell Physiol Biochem

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Background/Aims: Liver fibrosis is a complex process of tissue remodeling in response to injury. Hepatic macrophages have been identified as a key player in this process. As the largest lymphoid organ in the body, the spleen exerts both local and systemic effects on immune cell response. Splenectomy can improve hepatic function during the treatment of liver cirrhosis. However, whether the spleen influences disease progression through the modulation of hepatic macrophages remains unclear. Methods: We examined ex vivo hepatic macrophage responses from splenectomized or sham operated rats and performed splenocyte adoptive transfer studies, in combination with in vivo CCL2 blockade, in splenectomized or sham operated rats. Results: We found that splenectomy reduced fibrosis severity and monocyte/ macrophage infiltration within the injured liver. Splenectomy also reduced secretion of the monocyte chemokine CCL2 by hepatic macrophages. Ex vivo, splenocytes, especially splenic macrophages, promoted CCL2 secretion via upregulation of SOCS3 signaling in hepatic macrophages. Migration of splenic monocytes in response to conditioned medium from hepatic macrophages was inhibited by the blockade of SOCS3–CCL2–CCR2 signaling. Splenectomy also attenuated the establishment of an M1-dominant hepatic macrophage phenotype whilst the adoptive transfer of splenocytes could partly reverse this effect and exacerbate fibrosis. However, CCL2 blockade following adoptive splenocyte transfer restored the protective effects of splenectomy. Conclusion: Our study demonstrates that splenic macrophages can promote hepatic macrophage secretion of CCL2, which in turn facilitates monocyte recruitment and the establishment of an M1-dominant hepatic macrophage phenotype, and thus increase the severity of liver fibrosis.

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Section: Discussionmentioning

confidence: 99%

“…Since CCL2 production is correlated with SOCS3 activity [33], we postulated that hepatic CCL2 expression may be regulated by alterations in SOCS3 signaling. First we examined SOCS3 expression in liver sections through immunofluorescent co-staining of SOCS3 and CD68.…”

Section: Splenic Macrophages Isolated From Fibrotic Rats Promote Hepamentioning

confidence: 99%

The Spleen Promotes the Secretion of CCL2 and Supports an M1 Dominant Phenotype in Hepatic Macrophages During Liver Fibrosis

Wei

et al. 2018

Cell Physiol Biochem

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“…Fresh pancreatic tissue was minced and digested with 3 mg/ml collagenase A (Roche, Mannheim, Germany) for 15 min at 37°C. The digest was filtered through a 40-m cell strainer and washed with Hank's balanced salt solution containing 1.5% FCS, as described previously (16). Viability was ascertained using with 7-AAD and annexin V (BD Pharmingen, Franklin Lakes, NJ) double staining; specimens with Ն80% living cells were selected for examination.…”

Section: Animalsmentioning

confidence: 99%

“…Chemokine (C-C motif) ligand 2 (CCL2) is a small cytokine of the CC chemokine family, and its receptor (CCR2) plays an important role in the recruitment of monocytes, memory T cells, and peritoneal macrophages in inflammatory tissues (1,19,22). Recently we showed that CCL2-deficient mice are resistant to acute cerulein pancreatitis by affecting the migration of pathological TNF-␣-producing CD11b high /CD11c Ϫ / Gr-1 low macrophages (16). However, no studies on the role of the CCR2/CCL2 axis and its involvement in insulin secretion in chronic pancreatitis have been reported to date.…”

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confidence: 99%

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

Nakamura

Kanai²,

Saeki³

et al. 2013

American Journal of Physiology-Gastrointestinal and Liver Physi

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Glucagon-like 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-1(low) 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-1(high) cells, but not CD11b(+)/Gr-1(low) 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 cerulein-administered 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 pancreatitis-mediated hyperglycemia through the modulation of GLP-1 receptor expression and insulin secretion.

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“…Mice were fasted for 16 h before the experiment and received eight intra-peritoneal injections of cerulein at 50 µg/kg or 75 µg/kg at hourly intervals over 7 h [21]. Control mice were administered saline.…”

Section: Cerulein-induced Pancreatitismentioning

confidence: 99%

Exacerbated experimental pancreatitis in interleukin-19 knockout mice

Fujimoto¹,

Tsuneyama²,

Kuramoto³

et al. 2017

Glob Drugs Therap

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

Cited by 79 publications

References 36 publications

The Spleen Promotes the Secretion of CCL2 and Supports an M1 Dominant Phenotype in Hepatic Macrophages During Liver Fibrosis

The Spleen Promotes the Secretion of CCL2 and Supports an M1 Dominant Phenotype in Hepatic Macrophages During Liver Fibrosis

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

Exacerbated experimental pancreatitis in interleukin-19 knockout mice

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