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

BACKGROUND AND PURPOSE

Macrophage infiltration and activation is a critical step during acute pancreatitis (AP). We have shown that pancreas-specific D receptor signalling protects against AP severity. As it is unclear to what extent myeloid-specific D receptor mediates AP, we investigated the role of myeloid-specific D receptor signalling in AP.

EXPERIMENTAL APPROACH

Using wild-type and LysM D 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 D receptor expression was down-regulated in M1-polarized macrophages from murine bone marrows. During AP, myeloid-specific D receptor deletion worsened pancreatic injury, systematic inflammation and promoted macrophages to M1 phenotype. Furthermore, M1 macrophages from LysM D mice exhibited increased NADPH oxidase-induced oxidative stress and enhanced NF-κB and NLRP3 inflammasome activation. D 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 D receptor signalling controls pancreatic injury and systemic inflammation via inhibiting M1 macrophage, suggesting D receptor activation might serve as therapeutic target for AP.