PMID- 36108735 OWN - NLM STAT- MEDLINE DCOM- 20221006 LR - 20221006 IS - 1879-0712 (Electronic) IS - 0014-2999 (Linking) VI - 933 DP - 2022 Oct 15 TI - Geniposide inhibits SphK1 membrane targeting to restore macrophage polarization balance in collagen-induced arthritis mice. PG - 175271 LID - S0014-2999(22)00532-5 [pii] LID - 10.1016/j.ejphar.2022.175271 [doi] AB - Imbalance of macrophage polarization plays a critical role in the progression of rheumatoid arthritis (RA). Geniposide (GE) has been shown to exert anti-inflammatory effects. However, the effect of GE on macrophage polarization remains unclear. Here, we investigated the regulation of GE on the imbalance of macrophage polarization in RA and how it functions. We established a mouse model of collagen-induced arthritis (CIA) and isolated bone marrow-derived macrophages (BMDMs). The results confirmed that pro-inflammatory M1 macrophages were dominant in CIA mice, but the polarization imbalance of macrophages was restored to a certain extent after GE treatment. Furthermore, the membrane targeting of sphingosine kinase 1 (SphK1) was increased in BMDMs of CIA mice, as manifested by increased membrane and cytoplasmic expression of p-SphK1 and high secretion level of sphingosine-1-phosphate (S1P). RAW264.7 cells were stimulated with lipopolysaccharide (LPS)-interferon (IFN)-gamma or interleukin (IL)-4 to induce M1 or M2 phenotype, respectively, to revalidate the results obtained in BMDMs. The results again observed SphK1 membrane targeting in LPS-IFN-gamma-stimulated RAW264.7 cells. Selective inhibition of SphK1 by PF543 or inhibition of the S1P receptors by FTY720 both restored the proportion of M1 and M2 macrophages in LPS-IFN-gamma-stimulated RAW264.7 cells, confirming that SphK1 membrane targeting mediated a proportional imbalance in M1 and M2 macrophage polarization. In addition, GE inhibited SphK1 membrane targeting and kinase activity. Taken together, results confirmed that the inhibition of SphK1 membrane targeting by GE was responsible for restoring the polarization balance of macrophages in CIA mice. CI - Copyright (c) 2022. Published by Elsevier B.V. FAU - Gan, Pei-Rong AU - Gan PR AD - College of Pharmacy, Anhui University of Chinese Medicine, Qian Jiang Road 1, Hefei, 230012, China; Key Laboratory of Xin'an Medicine, Ministry of Education, Hefei, 230012, China; Anhui Province Key Laboratory of Research & Development of Chinese Medicine, Hefei, 230012, China. FAU - Wang, Rong-Hui AU - Wang RH AD - College of Pharmacy, Anhui University of Chinese Medicine, Qian Jiang Road 1, Hefei, 230012, China; Key Laboratory of Xin'an Medicine, Ministry of Education, Hefei, 230012, China; Anhui Province Key Laboratory of Research & Development of Chinese Medicine, Hefei, 230012, China. FAU - Deng, Ran AU - Deng R AD - Key Laboratory of Xin'an Medicine, Ministry of Education, Hefei, 230012, China; Anhui Province Key Laboratory of Research & Development of Chinese Medicine, Hefei, 230012, China; School of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, 230012, China. Electronic address: dengran94@aliyun.com. FAU - Wu, Hong AU - Wu H AD - College of Pharmacy, Anhui University of Chinese Medicine, Qian Jiang Road 1, Hefei, 230012, China; Key Laboratory of Xin'an Medicine, Ministry of Education, Hefei, 230012, China; Anhui Province Key Laboratory of Research & Development of Chinese Medicine, Hefei, 230012, China. Electronic address: wuhongprof@aliyun.com. FAU - Bu, Yan-Hong AU - Bu YH AD - College of Pharmacy, Anhui University of Chinese Medicine, Qian Jiang Road 1, Hefei, 230012, China; Key Laboratory of Xin'an Medicine, Ministry of Education, Hefei, 230012, China; Anhui Province Key Laboratory of Research & Development of Chinese Medicine, Hefei, 230012, China. FAU - Chen, Fang-Yuan AU - Chen FY AD - College of Pharmacy, Anhui University of Chinese Medicine, Qian Jiang Road 1, Hefei, 230012, China; Key Laboratory of Xin'an Medicine, Ministry of Education, Hefei, 230012, China; Anhui Province Key Laboratory of Research & Development of Chinese Medicine, Hefei, 230012, China. FAU - Dong, Xin-Tong AU - Dong XT AD - College of Pharmacy, Anhui University of Chinese Medicine, Qian Jiang Road 1, Hefei, 230012, China; Key Laboratory of Xin'an Medicine, Ministry of Education, Hefei, 230012, China; Anhui Province Key Laboratory of Research & Development of Chinese Medicine, Hefei, 230012, China. FAU - Ke, Jiang-Tao AU - Ke JT AD - College of Pharmacy, Anhui University of Chinese Medicine, Qian Jiang Road 1, Hefei, 230012, China; Key Laboratory of Xin'an Medicine, Ministry of Education, Hefei, 230012, China; Anhui Province Key Laboratory of Research & Development of Chinese Medicine, Hefei, 230012, China. LA - eng PT - Journal Article DEP - 20220913 PL - Netherlands TA - Eur J Pharmacol JT - European journal of pharmacology JID - 1254354 RN - 0 (Anti-Inflammatory Agents) RN - 0 (Iridoids) RN - 0 (Lipopolysaccharides) RN - 145295QLXY (geniposide) RN - 82115-62-6 (Interferon-gamma) RN - EC 2.7.1.- (Phosphotransferases (Alcohol Group Acceptor)) RN - EC 2.7.1.- (sphingosine kinase) RN - G926EC510T (Fingolimod Hydrochloride) SB - IM MH - Animals MH - Anti-Inflammatory Agents/pharmacology MH - *Arthritis, Experimental/drug therapy/metabolism MH - *Arthritis, Rheumatoid/metabolism MH - Fingolimod Hydrochloride/pharmacology MH - Interferon-gamma/pharmacology MH - Iridoids MH - Lipopolysaccharides/pharmacology MH - Macrophages MH - Mice MH - Phosphotransferases (Alcohol Group Acceptor) MH - Signal Transduction OTO - NOTNLM OT - Geniposide OT - Macrophage polarization OT - Membrane targeting OT - Rheumatoid arthritis OT - Sphingosine kinase 1 COIS- Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2022/09/16 06:00 MHDA- 2022/10/07 06:00 CRDT- 2022/09/15 19:23 PHST- 2022/07/07 00:00 [received] PHST- 2022/08/23 00:00 [revised] PHST- 2022/09/08 00:00 [accepted] PHST- 2022/09/16 06:00 [pubmed] PHST- 2022/10/07 06:00 [medline] PHST- 2022/09/15 19:23 [entrez] AID - S0014-2999(22)00532-5 [pii] AID - 10.1016/j.ejphar.2022.175271 [doi] PST - ppublish SO - Eur J Pharmacol. 2022 Oct 15;933:175271. doi: 10.1016/j.ejphar.2022.175271. Epub 2022 Sep 13.