PMID- 33617975 OWN - NLM STAT- MEDLINE DCOM- 20220119 LR - 20220119 IS - 1096-1186 (Electronic) IS - 1043-6618 (Linking) VI - 167 DP - 2021 May TI - Suppression of macrophage migration by down-regulating Src/FAK/P130Cas activation contributed to the anti-inflammatory activity of sinomenine. PG - 105513 LID - S1043-6618(21)00097-9 [pii] LID - 10.1016/j.phrs.2021.105513 [doi] AB - A large number of macrophages in inflamed sites not only amplify the severity of inflammatory responses but also contribute to the deleterious progression of many chronic inflammatory diseases, autoimmune diseases and cancers. Macrophage migration is a prerequisite for their entry into inflammatory sites and their participation of macrophages in the pathologic processes. Inhibition of macrophage migration is therefore a potential anti-inflammatory mechanism. Moreover, alleviation of inflammation also prevents the macrophages infiltration. Sinomenine (SIN) is an alkaloid derived from the Chinese medicinal plant Sinomenium acutum. It has multiple pharmacological effects, including anti-inflammation, immunosuppression, and anti-arthritis. However, its anti-inflammatory molecular mechanisms and effect on macrophage migration are not fully understood. The purpose of this research was to investigate the pharmacological effects and the molecular mechanism of SIN on macrophage migration in vivo and in vitro as well as to elucidate its anti-inflammatory mechanisms associated with macrophage migration. Our results showed that SIN reduced the number of RAW264.7 cells migrating into inflammatory paws and blocked lipopolysaccharide (LPS)-induced RAW264.7 cells and bone marrow-derived macrophages (BMDMs) migration in vitro. Furthermore, SIN attenuated the 3D mesenchymal migration of BMDMs. The absence of macrophage migration after circulatory and periphery macrophages depletion led to a reduction in the severity of inflammatory response. In macrophages depleted (macrophages(-/-)) mice, as inflammatory severity decreased, RAW264.7 cells migration was suppressed. A non-obvious effect of SIN on the inflammatory response was found in macrophages(-/-) mice, while the inhibitory effect of SIN on RAW264.7 cells migration was still observed. Furthermore, the migration of RAW264.7 cells pre-treated with SIN was suppressed in normal mice. Finally, Src/focal adhesion kinase (FAK)/P130Cas axis activation, which supports macrophages mesenchymal migration, and iNOS expression, NO production, integrin alphaV and in integrin beta3 expressions, which promote Src/FAK/P130Cas activation, were down-regulated by SIN. However, SIN had no obvious effect on the expression of the monocyte chemoattractant protein-1 (MCP-1), which is an important chemokine for macrophage migration. These results indicated that SIN significantly inhibited macrophage mesenchymal migration by down-regulating on Src/FAK/P130Cas axis activation. There was a mutual regulatory correlation between the inflammatory response and macrophage migration, and the effects of SIN on macrophage migration were involved in its anti-inflammatory activity. CI - Copyright (c) 2021 Elsevier Ltd. All rights reserved. FAU - Gao, Wan-Jiao AU - Gao WJ AD - Faculty of Chinese Medicine and State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macao, PR China. FAU - Liu, Jian-Xin AU - Liu JX AD - School of Pharmaceutical Sciences, Hunan University of Medicine, Huaihua City, Hunan Province, PR China. FAU - Xie, Yie AU - Xie Y AD - Faculty of Chinese Medicine and State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macao, PR China. FAU - Luo, Pei AU - Luo P AD - Faculty of Chinese Medicine and State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macao, PR China. FAU - Liu, Zhong-Qiu AU - Liu ZQ AD - Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China, Guangzhou University of Chinese Medicine, Guangzhou, PR China. FAU - Liu, Liang AU - Liu L AD - Faculty of Chinese Medicine and State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macao, PR China; Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China, Guangzhou University of Chinese Medicine, Guangzhou, PR China. Electronic address: lliu@must.edu.mo. FAU - Zhou, Hua AU - Zhou H AD - Faculty of Chinese Medicine and State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macao, PR China; Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China, Guangzhou University of Chinese Medicine, Guangzhou, PR China. Electronic address: hzhou@must.edu.mo. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20210220 PL - Netherlands TA - Pharmacol Res JT - Pharmacological research JID - 8907422 RN - 0 (Anti-Inflammatory Agents) RN - 0 (Crk-Associated Substrate Protein) RN - 0 (Morphinans) RN - 63LT81K70N (sinomenine) RN - EC 2.7.10.2 (Focal Adhesion Kinase 1) RN - EC 2.7.10.2 (Ptk2 protein, mouse) RN - EC 2.7.10.2 (src-Family Kinases) SB - IM MH - Animals MH - Anti-Inflammatory Agents/chemistry/*pharmacology MH - Cell Movement/*drug effects MH - Crk-Associated Substrate Protein/metabolism MH - Enzyme Activation/*drug effects MH - Focal Adhesion Kinase 1/metabolism MH - Macrophages/cytology/*drug effects/metabolism MH - Mice MH - Morphinans/chemistry/*pharmacology MH - RAW 264.7 Cells MH - Signal Transduction/drug effects MH - Sinomenium/chemistry MH - src-Family Kinases/metabolism OTO - NOTNLM OT - Inflammation OT - Macrophage mesenchymal migration OT - Macrophage migration OT - Macrophages depletion OT - Sinomenine EDAT- 2021/02/23 06:00 MHDA- 2022/01/20 06:00 CRDT- 2021/02/22 20:11 PHST- 2021/01/28 00:00 [received] PHST- 2021/02/18 00:00 [revised] PHST- 2021/02/18 00:00 [accepted] PHST- 2021/02/23 06:00 [pubmed] PHST- 2022/01/20 06:00 [medline] PHST- 2021/02/22 20:11 [entrez] AID - S1043-6618(21)00097-9 [pii] AID - 10.1016/j.phrs.2021.105513 [doi] PST - ppublish SO - Pharmacol Res. 2021 May;167:105513. doi: 10.1016/j.phrs.2021.105513. Epub 2021 Feb 20.