Dataset Information

Myeloid-specific dopamine D₂ receptor signalling controls inflammation in acute pancreatitis via inhibiting M1 macrophage.

ABSTRACT:

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.

SUBMITTER: Han X

PROVIDER: S-EPMC7280007 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundNonresolving inflammation is a major driver of disease and needs to be taken seriously. Hypoxia-inducible factor (HIF) is closely associated with inflammation. Hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHIs), as stabilizers of HIF, have recently been reported to have the ability to block inflammation. We used MK8617, a novel HIF-PHI, to study its effect on macrophage inflammation and to explore its possible mechanisms.MethodsCell viability after MK8617 and lipopolysaccharide (LPS) addition was assessed by Cell Counting Kit-8 (CCK8) to find the appropriate drug concentration. MK8617 pretreated or unpretreated cells were then stimulated with LPS to induce macrophage polarization and inflammation. Inflammatory indicators in cells were assessed by real-time quantitative reverse-transcription polymerase chain reaction (qRT-PCR), western blot (WB) and immunofluorescence (IF). The level of uridine diphosphate glucose (UDPG) in the cell supernatant was measured by ELISA. Purinergic G protein-coupled receptor P2Y14, as well as hypoxia-inducible factor-1α (HIF-1α) and glycogen synthase 1 (GYS1) were detected by qRT-PCR and WB. After UDPG inhibition with glycogen phosphorylase inhibitor (GPI) or knockdown of HIF-1α and GYS1 with lentivirus, P2Y14 and inflammatory indexes of macrophages were detected by qRT-PCR and WB.ResultsMK8617 reduced LPS-induced release of pro-inflammatory factors as well as UDPG secretion and P2Y14 expression. UDPG upregulated P2Y14 and inflammatory indicators, while inhibition of UDPG suppressed LPS-induced inflammation. In addition, HIF-1α directly regulated GYS1, which encoded glycogen synthase, an enzyme that mediated the synthesis of glycogen by UDPG, thereby affecting UDPG secretion. Knockdown of HIF-1α and GYS1 disrupted the anti-inflammatory effect of MK8617.ConclusionsOur study demonstrated the role of MK8617 in macrophage inflammation and revealed that its mechanism of action may be related to the HIF-1α/GYS1/UDPG/P2Y14 pathway, providing new therapeutic ideas for the study of inflammation.

Dataset Information

Myeloid-specific dopamine D₂ receptor signalling controls inflammation in acute pancreatitis via inhibiting M1 macrophage.

Background and purpose

Experimental approach

Key results

Conclusion and implications

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OmicsDI is part of the ELIXIR infrastructure

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Myeloid-specific dopamine D2 receptor signalling controls inflammation in acute pancreatitis via inhibiting M1 macrophage.

Background and purpose

Experimental approach

Key results

Conclusion and implications

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OmicsDI is part of the ELIXIR infrastructure

Tweets

Myeloid-specific dopamine D₂ receptor signalling controls inflammation in acute pancreatitis via inhibiting M1 macrophage.