Macrophages-derived p38α promotes the experimental severe acute pancreatitis by regulating inflammation and autophagy

• Published in: International immunopharmacology 2019-12, Vol.77, p.105940-105940, Article 105940
• Main Authors: Fan, Hui-Ning, Chen, Wei, Fan, Li-Na, Wu, Jing-Tong, Zhu, Jin-Shui, Zhang, Jing
• Format: Article
• Language: English
• Subjects: Acute Disease; Acute pancreatitis; Animal models; Animals; Autophagy; Autophagy - physiology; Caspase 1 - metabolism; Caspase-1; Cytokines; Cytokines - metabolism; Disease Models, Animal; Enzyme-linked immunosorbent assay; Gene expression; Health risks; IL-1β; Imidazoles - pharmacology; Immunohistochemistry; Inflammation; Inflammation - metabolism; Interleukin 17; Interleukin 18; Macrophages; Macrophages - drug effects; Macrophages - metabolism; Male; MAP kinase; Mice; Mice, Inbred C57BL; Microtubule-Associated Proteins - metabolism; Monocyte chemoattractant protein 1; mRNA; p38 Mitogen-Activated Protein Kinases - metabolism; P38α; Pancreas; Pancreas - metabolism; Pancreatitis; Pancreatitis - metabolism; Pancreatitis - pathology; Phagocytosis; Protein expression; Proteins; Pyridines - pharmacology; Serum levels; Signal Transduction - physiology; Transmission electron microscopy; Tumor necrosis factor-α; ULK1; Western blotting
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/j.intimp.2019.105940

•p38α conditionally knocked out in macrophages can alleviate the severity of SAP.•p38α in macrophages may affect autophagy by regulating ULK1 expression in SAP, providing a new understanding of the mechanistic basis of the inflammatory process. Severe acute pancreatitis (SAP) is a common threat to human health. In the present study, we aimed to investigate the underlying mechanisms by which p38α in macrophages contributes to SAP. We used conditional knockout of p38α in macrophages and p38 MAPK inhibitors to understand the effects of p38α in macrophages on caerulein-induced inflammatory responses in SAP mice models. Wild-type (WT) mice were randomly divided into three groups: a control group, SAP group, and SAP + p38MAPK inhibitor (SB203580) group, and mice with a conditional knockout (KO) of p38α in macrophages were included in a KO + SAP group. We evaluated pancreatic pathology and ultra-structure by hematoxylin and eosin staining and transmission electron microscopy. The pulmonary wet-to-dry weight ratio was calculated. The serum levels of TNF-α and IL-1β were determined by ELISA. The mRNA and protein expression of inflammatory cytokines TNF-α, IL-1β, IL-17, IL-18, MIF, and MCP-1 in pancreatic tissues were tested by qRT-PCR and immunohistochemistry analysis. The protein expression of p38, caspase-1, ULK1, LC3B and p62 in pancreatic tissues was examined by Western blotting. The results indicated that the severity of SAP as well as the expression of the cytokines TNF-α, IL-1β, IL-17, IL-18 and MCP-1 were higher in the SAP group than those in the control group, but were lower in the SAP + SB203580 and KO + SAP groups as compared with the SAP group. The protein expression of p38, caspase-1, LC3B and p62 was increased in the SAP group than that in the control group, but this result was reversed in the SAP + SB203580 and KO + SAP groups as compared with the SAP group. In addition, the ULK1 level was significantly lower in the SAP group than that in the control group, but was increased in the SAP + SB203580 and KO + SAP groups as compared with the SAP group. Our findings demonstrated that, macrophage derived p38α promoted the experimental severe acute pancreatitis by regulating inflammation and autophagy.