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Updated: Dec 28, 2025
Preparing a Mice Model of Severe Acute Pancreatitis via a Combination of Caerulein and Lipopolysaccharide Intraperitoneal Injection
Published on: May 10, 2024
Myeloid-specific dopamine D2 receptor signalling controls inflammation in acute pancreatitis via inhibiting M1
Xiao Han1,2, Jianbo Ni1,2, Zengkai Wu1,2
1Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Background And Purpose:
Macrophage infiltration and activation is a critical step during acute pancreatitis (AP). We have shown that pancreas-specific D2 receptor signalling protects against AP severity. As it is unclear to what extent myeloid-specific D2 receptor mediates AP, we investigated the role of myeloid-specific D2 receptor signalling in AP.
Experimental Approach:
Using wild-type and LysM+/cre D2 fl/fl mice, AP was induced by l-arginine, caerulein and LPS. Murine bone marrow-derived macrophages and human peripheral blood mononuclear cells (PBMCs) were isolated, cultured and then induced to M1 phenotype. AP severity was assessed by measurements of serum amylase and lipase and histological grading. Macrophage phenotype was assessed by flow cytometry and qRT-PCR. NADPH oxidase-induced oxidative stress and NF-κB and NLRP3 inflammasome signalling pathways were also evaluated.
Key Results:
We found that dopaminergic system was activated and dopamine reduced inflammatory cytokine expression in M1-polarized macrophages from human PBMCs. Dopaminergic synthesis was also activated, but D2 receptor expression was down-regulated in M1-polarized macrophages from murine bone marrows. During AP, myeloid-specific D2 receptor deletion worsened pancreatic injury, systematic inflammation and promoted macrophages to M1 phenotype. Furthermore, M1 macrophages from LysM+/cre D2 fl/fl mice exhibited increased NADPH oxidase-induced oxidative stress and enhanced NF-κB and NLRP3 inflammasome activation. D2 receptor activation inhibited M1 macrophage polarization, oxidative stress-induced NF-κB and NLRP3 inflammasome activation.
Conclusion And Implications:
Our data for the first time showed that myeloid-specific D2 receptor signalling controls pancreatic injury and systemic inflammation via inhibiting M1 macrophage, suggesting D2 receptor activation might serve as therapeutic target for AP.
Insights
Myeloid-specific dopamine D2 receptor signaling protects against acute pancreatitis (AP) by inhibiting M1 macrophage activation. Activating D2 receptors may offer a new therapeutic strategy for AP.
Area of Science:
- Immunology
- Gastroenterology
- Pharmacology
Background:
- Macrophage activation is crucial in acute pancreatitis (AP) pathogenesis.
- Pancreas-specific dopamine D2 receptor signaling confers protection against AP.
- The role of myeloid-specific D2 receptor in AP remains unclear.
Purpose of the Study:
- To investigate the role of myeloid-specific dopamine D2 receptor signaling in AP.
- To determine if D2 receptor activation influences macrophage polarization and inflammatory pathways in AP.
Main Methods:
- Acute pancreatitis was induced in wild-type and myeloid-specific D2 receptor knockout mice using l-arginine, caerulein, and LPS.
- Murine bone marrow-derived macrophages and human peripheral blood mononuclear cells (PBMCs) were polarized to M1 phenotype.
- AP severity, macrophage phenotype, oxidative stress, and inflammatory signaling pathways (NF-κB, NLRP3 inflammasome) were assessed.
Main Results:
- Dopamine D2 receptor signaling inhibited inflammatory cytokine expression in M1-polarized human macrophages.
- Myeloid-specific D2 receptor deletion exacerbated AP severity, systemic inflammation, and promoted M1 macrophage polarization.
- M1 macrophages from knockout mice showed increased oxidative stress and enhanced NF-κB and NLRP3 inflammasome activation.
- D2 receptor activation suppressed M1 macrophage polarization and associated inflammatory signaling.
Conclusions:
- Myeloid-specific D2 receptor signaling plays a critical role in controlling pancreatic injury and systemic inflammation during AP.
- Inhibition of M1 macrophage polarization by D2 receptor activation is a key mechanism.
- Dopamine D2 receptor activation presents a potential therapeutic target for managing AP.
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