Dimethyl itaconate protects against lipopolysaccharide-induced endometritis by inhibition of TLR4/NF-κB and activation of Nrf2/HO-1 signaling pathway in mice

Document Type: Original Article

Authors

1 Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Jilin University, Changchun, Jilin Province 130062, People, Republic of China

2 Department of Otolaryngology, Head and Neck Surgery, The Second Affiliated Hospital of Jilin University, Changchun, China

10.22038/ijbms.2020.44151.10346

Abstract

Objective(s): Endometritis is the inflammation of the uterine lining that is associated with infertility. It affects milk production and reproductive performance and leads to huge economic losses in dairy cows. Dimethyl itaconate (DI), a promising chemical agent, has recently been proved to have multiple health-promoting effects. However, the effects of DI on endometritis remain to be unknown.
Materials and Methods: In this study, we assessed the anti-inflammatory effects of DI on Lipopolysaccharide (LPS)-induced endometritis in mice. The endometritis was induced by LPS treatment for 24 hr, and DI was given 24 hr before induction of LPS.
Results: As a result, DI administered mice significantly suffered less impairment of uterine tissue and less recruitment of inflammatory cells than LPS administered mice. In addition, DI markedly inhibited uterine myeloperoxidase (MPO) activity and pro-inflammatory cytokines of tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) induced by LPS. Moreover, LPS-induced toll-like receptor 4/ nuclear factor-kappa B (TLR4/NF-κB) activation was suppressed by DI. In addition, the expressions of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase (HO-1) were upregulated by DI.
Conclusion: These findings suggest that DI has anti-inflammatory functions in the LPS-induced mice and may be a therapeutic agent against endometritis.

Keywords


1. Sheldon IM, Dobson H. Postpartum uterine health in cattle. Anim Reprod Sci 2004;82-83:295-306.
2. Moustafa S, Joseph DN, Taylor RN, Whirledge S. New Models of LPS-Induced Implantation Loss Reveal Insights into the Inflammatory Response. Am J Reprod Immunol 2019:e13082.
3. Guha M, Mackman N. LPS induction of gene expression in human monocytes. Cell Signal 2001;13:85-94.
4. Bambouskova M, Gorvel L, Lampropoulou V, Sergushichev A, Loginicheva E, Johnson K, et al. Electrophilic properties of itaconate and derivatives regulate the IkappaBzeta-ATF3 inflammatory axis. Nature 2018;556:501-504.
5. Lampropoulou V, Sergushichev A, Bambouskova M, Nair S, Vincent EE, Loginicheva E, et al. Itaconate links inhibition of succinate dehydrogenase with macrophage metabolic remodeling and regulation of inflammation. Cell Metab 2016;24:158-166.
6. Weiss JM, Davies LC, Karwan M, Ileva L, Ozaki MK, Cheng RY, et al. Itaconic acid mediates crosstalk between macrophage metabolism and peritoneal tumors. J Clin Invest 2018;128:3794-3805.
7. Hammerer F, Chang JH, Duncan D, Castaneda Ruiz A, Auclair K. Small molecule restores itaconate sensitivity in salmonella enterica: a potential new approach to treating bacterial infections. Chembiochem 2016;17:1513-1517.
8. Mills EL, Ryan DG, Prag HA, Dikovskaya D, Menon D, Zaslona Z, etal Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1. Nature 2018;556:113-117.
9. Cordes T, Wallace M, Michelucci A, Divakaruni AS, Sapcariu SC, Sousa C, et al. Immunoresponsive gene 1 and itaconate inhibit succinate dehydrogenase to modulate intracellular succinate levels. J Biol Chem 2016;291:14274-14284.
10. Wu H, Jiang K, Yin N, Ma X, Zhao G, Qiu C, et al. Thymol mitigates lipopolysaccharide-induced endometritis by regulating the TLR4- and ROS-mediated NF-kappa B signaling pathways. Oncotarget 2017;8:20042-20055.
11. Fu K, Lv X, Li W, Wang Y, Li H, Tian W, etal Berberine hydrochloride attenuates lipopolysaccharide-induced endometritis in mice by suppressing activation of NF-kappa B signal pathway. Int Immunopharmacol. 2015;24:128-132.
12. Zhou M, Yi Y, Hong L. Oridonin ameliorates lipopolysaccharide-induced endometritis in mice via inhibition of the TLR-4/NF-kappaBpathway. Inflammation 2019;42:81-90.
13. Lv X, Fu K, Li W, Wang Y, Wang J, Li H, et al. TIIA attenuates LPS-induced mouse endometritis by suppressing the NF-kappa B signaling pathway. Can J Physiol Pharmacol 2015;93:967-971.
14. Miranda-CasoLuengo R, Lu J, Williams EJ, Miranda-CasoLuengo AA, Carrington SD, Evans ACO, et al. Delayed differentiation of vaginal and uterine microbiomes in dairy cows developing postpartum endometritis. PLoS One 2019;14:e0200974.
15. Bhadaniya AR, Prasad MC, Savsani HH, Kalaria VA, Fefar DT, Mathpati BS, et al. Pro-inflammatory cytokine expression studies of subclinical and clinical endometritis in endometrial tissues of buffaloes. Trop Anim Health Prod 2019; 51:1161-1166.
16. Sheldon IM, Cronin J, Goetze L, Donofrio G, Schuberth HJ. Defining postpartum uterine disease and the mechanisms of infection and immunity in the female reproductive tract in cattle. Biol Reprod 2009;81:1025-1032.
17. Hu XY, Li DP, Wang JX, Guo J, Li YY, Cao YG, et al. Melatonin inhibits endoplasmic reticulum stress-associated TXNIP/NLRP3 inflammasome activation in lipopolysaccharide-induced endometritis in mice. Int Immunopharmacol 2018;64:101-109.
18. Zhao C, Cui Z, Zhao X, Zhang J, Zhang L, Tian Y, et al. Enhanced itaconic acid production in Yarrowia lipolytica via heterologous expression of a mitochondrial transporter MTT. Appl Microbiol Biotechnol 2019; 103:2181-2192.
19. Yu XH, Zhang DW, Zheng XL, Tang CK. Itaconate: an emerging determinant of inflammation in activated macrophages. Immunol Cell Biol 2019; 97:134-141.
20. Perico L, Wyatt CM, Benigni A. A new BEACON of hope for the treatment of inflammation? The endogenous metabolite itaconate as an alternative activator of the KEAP1-Nrf2 system. Kidney Int 2018;94:646-649.
21. Bordon Y. Itaconate charges down inflammation. Nat Rev Immunol 2018;18:360-361.
22. Maruyama Y, Lindholm B, Stenvinkel P. Inflammation and oxidative stress in ESRD-the role of myeloperoxidase. J Nephrol 2004;17 Suppl 8:S72-76.
23. Jiang C, Ting AT, Seed B. PPAR-gamma agonists inhibit production of monocyte inflammatory cytokines. Nature 1998;391:82-86.
24. Ghosh S, Hayden MS. New regulators of NF-kappa B in inflammation. Nat Rev Immunol 2008;8:837-848.
25. Taniguchi K, Karin M. NF-kappa B, inflammation, immunity and cancer: coming of age. Nat Rev Immunol 2018;18:309-324.
26. Baeuerle PA, Baltimore D. I kappa B: a specific inhibitor of the NF-kappa B transcription factor. Science 1988;242:540-546.
27. Yan Z, Huang C, Huang G, Wu Y, Wang J, Yi J, et al. Jiedu Huoxue decoction improves inflammation in rat type III prostatitis: The importance of the NF-kappa B signalling pathway. Andrologia 2019:e13245.
28. Zerfaoui M, Errami Y, Naura AS, Suzuki Y, Kim H, Ju J, et al. Poly(ADP-ribose) polymerase-1 is a determining factor in Crm1-mediated nuclear export and retention of p65 NF-kappa B upon TLR4 stimulation. J Immunol 2010;185:1894-902.
29. Wu TY, Khor TO, Saw CL, Loh SC, Chen AI, Lim SS, et al. Anti-inflammatory/Anti-oxidative stress activities and differential regulation of Nrf2-mediated genes by non-polar fractions of tea Chrysanthemum zawadskii and licorice Glycyrrhiza uralensis. AAPS J 2011;13:1-13.
30. Zheng Y, Zhu G, He J, Wang G, Li D, Zhang F. Icariin targets Nrf2 signaling to inhibit microglia-mediated neuroinflammation. Int Immunopharmacol 2019;73:304-311.
31. Wang J, Wang W, Pang Y. Saikosaponin A inhibits LPS-induced endometritis in mice through activating Nrf2 signaling pathway. Inflammation 2018;41:1508-1514.
32. Li J, Ichikawa T, Villacorta L, Janicki JS, Brower GL, Yamamoto M, et al. Nrf2 protects against maladaptive cardiac responses to hemodynamic stress. Arterioscler Thromb Vasc Biol 2009;29:1843-1850.
33. Kim KH, Lyu JH, Koo ST, Oh SR, Lee HK, Ahn KS, et al. MyD88 is a mediator for the activation of Nrf2. Biochem Biophys Res Commun 2011; 404:46-51.
34. Mukherjee S, Ghosh S, Choudhury S, Adhikary A, Manna K, Dey S, et al. Pomegranate reverses methotrexate-induced oxidative stress and apoptosis in hepatocytes by modulating Nrf2-NF-kappa B pathways. J Nutr Biochem 2013;24:2040-2050.
35. Harvey CJ, Thimmulappa RK, Singh A, Blake DJ, Ling G, Wakabayashi N, et al. Nrf2-regulated glutathione recycling independent of biosynthesis is critical for cell survival during oxidative stress. Free Radical Bio Med 2009;46:443-453.