Abstract
Background
Curcumin is a diketone compound extracted from the rhizomes of some plants in the Zingiberaceae and Araceae family. It possesses a variety of biological activities, including antioxidant, anti-inflammatory and anti-cancer properties. However, the cellular and molecular antipruritic mechanisms of curcumin remain to be explored.
Objective
Our objective was to study the role of curcumin in pruritus and determine whether its antipruritic effect is related to MrgprB2 receptor.
Methods
The effect of curcumin on pruritus in mice was examined by scratching behavior test. The antipruritic mechanism of curcumin was explored by using transgenic mice (MrgprB2−/− mice, MrgprB2CreTd/tomato mice), histological analysis, western blot and immunofluorescence. In addition, the relationship between curcumin and MrgprB2/X2 receptor was studied in vitro by using calcium imaging, plasmid transfection and molecular docking
Results
In the current study, we found that curcumin had obvious antipruritic effect. Its antipruritic effect was related to the regulation of MrgprB2 receptor activation and mast cells tryptase release. In vitro, mouse peritoneal mast cells activated by compound 48/80 could be inhibited by curcumin. In addition, curcumin was also found to suppress the calcium flux in MrgprX2 or MrgprB2-overexpression HEK cells induced by compound 48/80, substance P, and PAMP 9-20, displaying the specific relation with the MrgprB2/X2 receptor. Moreover, molecular docking results showed that curcumin had affinity to MrgprX2 protein.
Conclusions
Overall, these results indicated that curcumin has the potential to treat pruritus induced by mast cell MrgprB2 receptor.
Similar content being viewed by others
Data availability
All data relevant to the study are included in the article or uploaded as supplementary information. Data is available upon request.
References
Akpinar A, Calisir M, Cansın Karakan N, Lektemur Alpan A, Goze F, Poyraz O. Effects of curcumin on alveolar bone loss in experimental periodontitis in rats: a morphometric and histopathologic study. Int J Vitam Nutr Res. 2017;87(5–6):262–70. https://doi.org/10.1024/0300-9831/a000243.
Anand P, Kunnumakkara AB, Newman RA, Aggarwal BB. Bioavailability of curcumin: problems and promises. Mol Pharm. 2007;4(6):807–18. https://doi.org/10.1021/mp700113r.
Barnes PJ. Immunology of asthma and chronic obstructive pulmonary disease. Nat Rev Immunol. 2008;8:183–92. https://doi.org/10.1038/nri2254. (Epub 2008 Feb 15).
Callahan BN, Kammala AK, Syed M, Yang C, Occhiuto CJ, Nellutla R, Chumanevich AP, Oskeritzian CA, Das R, Subramanian H. Osthole, a natural plant derivative inhibits MRGPRX2 induced mast cell responses. Front Immunol. 2020;11:703. https://doi.org/10.3389/fimmu.2020.00703.
Choi YH, Yan GH, Chai OH, Song CH. Inhibitory effects of curcumin on passive cutaneous anaphylactoid response and compound 48/80-induced mast cell activation. Anat Cell Biol. 2010;43(1):36–43. https://doi.org/10.5115/acb.2010.43.1.36.
Dong XT, Dong XZ. Peripheral and central mechanisms of itch. Neuron. 2018;98:482–94. https://doi.org/10.1016/j.neuron.2018.03.023.
Erickson S, Nahmias Z, Rosman IS, Kim BS. Immunomodulating agents as antipruritics [J]. Dermatol Clin. 2018;36:325–34. https://doi.org/10.1016/j.det.2018.02.014.
Foster B, Schwartz LB, Devouassoux G, Metcalfe DD, Prussin C. Characterization of mast-cell tryptase-expressing peripheral blood cells as basophils. J Allergy Clin Immunol. 2002;109(2):287–93. https://doi.org/10.1067/mai.2002.121454.
Fu M, Fu S, Ni S, Wang D, Hong T. Inhibitory effects of bisdemethoxycurcumin on mast cell-mediated allergic diseases. Int Immunopharmacol. 2018;65:182–9. https://doi.org/10.1016/j.intimp.2018.10.005.
Fujisawa D, Kashiwakura J, Kita H, Kikukawa Y, Fujitani Y, Sasaki-Sakamoto T, Kuroda K, Nunomura S, Hayama K, Terui T, Ra C, Okayama Y. Expression of Mas-related gene X2 on mast cells is upregulated in the skin of patients with severe chronic urticarial. J Allergy Clin Immunol. 2014;134:622-633.e9. https://doi.org/10.1016/j.jaci.2014.05.004.
Galli SJ, Tsai M. IgE and mast cells in allergic disease. Nat Med. 2012;18:693–704. https://doi.org/10.1038/nm.2755.
Gaudenzio N, Sibilano R, Marichal T, Starkl P, Reber LL, Cenac N, McNeil BD, Dong X, Hernandez JD, Sagi-Eisenberg R, Hammel I, Roers A, Valitutti S, Tsai M, Espinosa E, Galli SJ. Different activation signals induce distinct mast cell degranulation strategies. J Clin Invest. 2016;126:3981–98. https://doi.org/10.1172/JCI85538.
Green DP, Limjunyawong N, Gour N, Pundir P, Dong X. A mast-cell-specific receptor mediates neurogenic inflammation and pain. Neuron. 2019;101(3):412-420.e3. https://doi.org/10.1016/j.neuron.2019.01.012.
Gupta K, Harvima IT. Mast cell-neural interactions contribute to pain and itch. Immunol Rev. 2018;282:168–87. https://doi.org/10.1111/imr.12622.
Hamed AMR, Abdel-Shafi IR, Elsayed MDA, Mahfoz AM, Tawfeek SE, Abdeltawab MSA. Investigation of the effect of curcumin on oxidative stress, local inflammatory response, COX-2 expression, and microvessel density in trichinella spiralis induced enteritis. Myosit Myocard Mice Helminthol. 2022;59(1):18–36. https://doi.org/10.2478/helm-2022-0002.
Hao Y, Peng B, Che D, Zheng Y, Kong S, Liu R, Shi J, Han H, Wang J, Cao J, Zhang Y, Gao J, He L, Geng S. Imiquimod-relateddermatitisismainlymediatedbymastcelldegranulationviaMas-relatedG-proteincoupledreceptorB2. IntImmunopharmacol. 2020;81:106258. https://doi.org/10.1016/j.intimp.2020.106258.
He Y, Yue Y, Zheng X, Zhang K, Chen S, Du Z. Curcumin, inflammation, and chronic diseases: how are they linked? Molecules. 2015;20:9183–213. https://doi.org/10.3390/molecules20059183.
Hellman L, Akula S, Fu Z, Wernersson S. Mast cell and basophil granule proteases-in vivo targets and function. Front Immunol. 2022;13:918305. https://doi.org/10.3389/fimmu.2022.918305.
Heppner TJ, Fiekers JF. Compound 48/80 blocks transmission and increases the excitability of ganglion neurons. Eur J Pharmacol. 1992;213(3):427–34. https://doi.org/10.1016/0014-2999(92)90632-e.
Ipar VS, Dsouza A, Devarajan PV. Enhancing curcumin oral bioavailability through nanoformulations. Eur J Drug Metab Pharmacokinet. 2019;44(4):459–80. https://doi.org/10.1007/s13318-019-00545-z.
Jiang Y, Ye F, Du Y, Zong Y, Tang Z. P2X7R in mast cells is a potential target for salicylic acid and aspirin in treatment of inflammatory pain. J Inflamm Res. 2021;14:2913–31. https://doi.org/10.2147/JIR.S313348.
Kang D, Li B, Luo L, Jiang W, Lu Q, Rong M, Lai R. Curcumin shows excellent therapeutic effect on psoriasis in mouse model. Biochimie. 2016;123:73–80. https://doi.org/10.1016/j.biochi.2016.01.013.
Khatri DK, Juvekar AR. Neuroprotective effect of curcumin as evinced by abrogation of rotenone-induced motor deficits, oxidative and mitochondrial dysfunctions in mouse model of Parkinson’s disease. Pharmacol Biochem Behav. 2016;150–151:39–47. https://doi.org/10.1016/j.pbb.2016.09.002.
Kim HS, Kawakami Y, Kasakura K, Kawakami T. Recent advances in mast cell activation and regulation. F1000Res. 2020;9:196.
Kinney SR, Carlson L, Ser-Dolansky J, Thompson C, Shah S, Gambrah A, Xing W, Schneider SS, Mathias CB. Curcumin ingestion inhibits mastocytosis and suppresses intestinal anaphylaxis in a murine model of food allergy. PLoS ONE. 2015;10(7):0132467. https://doi.org/10.1371/journal.pone.0132467.
Kong ZL, Sudirman S, Lin HJ, Chen WN. In vitro anti-inflammatory effects of curcumin on mast cell-mediated allergic responses via inhibiting FcεRI protein expression and protein kinase C delta translocation. Cytotechnology. 2020;72(1):81–95. https://doi.org/10.1007/s10616-019-00359-6.
Kühn H, Kolkhir P, Babina M, Düll M, Frischbutter S, Fok JS, Jiao Q, Metz M, Scheffel J, Wolf K, Kremer AE, Maurer M. Mas-related G protein-coupled receptor X2 and its activators in dermatologic allergies. J Allergy Clin Immunol. 2021;147(2):456–69. https://doi.org/10.1016/j.jaci.2020.08.027.
Kurd SK, Smith N, VanVoorhees A, Troxel AB, Badmaev V, Seykora JT, Gelfand JM. Oral curcumin in the treatment of moderate to severe psoriasis vulgaris: a prospective clinical trial. J Am Acad Dermatol. 2008;58:625–31. https://doi.org/10.1016/j.jaad.2007.12.035.
Lee JH, Kim JW, Ko NY, Mun SH, Her E, Kim BK, Han JW, Lee HY, Beaven MA, Kim YM, Choi WS. Curcumin, a constituent of curry, suppresses IgE-mediated allergic response and mast cell activation at the level of Syk. J Allergy Clin Immunol. 2008;121(5):1225–31. https://doi.org/10.1016/j.jaci.2007.12.1160.
Lestari ML, Indrayanto G. Curcumin. Profiles Drug Subst Excip Relat Methodol. 2014;39:113–204. https://doi.org/10.1016/B978-0-12-800173-8.00003-9.
Manorak W, Idahosa C, Gupta K, Roy S, Panettieri R Jr, Ali H. Upregulation of Mas-related G Protein coupled receptor X2 in asthmatic lung mast cells and its activation by the novel neuropeptide hemokinin-1. Respir Res. 2018;19:1. https://doi.org/10.1186/s12931-017-0698-3.
Martin SF. New concept in cutaneous allergy. Contact Dermatitis. 2015;72:2–10. https://doi.org/10.1111/cod.12311.
McNeil BD, Pundir P, Meeker S, Han L, Undem BJ, Kulka M, Dong X. Identification of a mast-cell-specific receptor crucial for pseudo-allergic drug reactions. Nature. 2015;519:237–41. https://doi.org/10.1038/nature14022.
Meixiong J, Anderson M, Limjunyawong N, Sabbagh MF, Hu E, Mack MR, Oetjen LK, Wang F, Kim BS, Dong X. Activation of mast-cell-expressed mas-related G-protein-coupled receptors drives non-histaminergic itch. Immunity. 2019;50:1163–71. https://doi.org/10.1016/j.immuni.2019.03.013.
Menon VP, Sudheer AR. Antioxidant and anti-inflammatory properties of curcumin. Adv Exp Med Biol. 2007;595:105–25. https://doi.org/10.1007/978-0-387-46401-5_3.
Muto Y, Wang Z, Vanderberghe M, Two A, Gallo RL, Di Nardo A. Mast cells are key mediators of cathelicidin-initiated skin inflammation in rosacea. J Invest Dermatol. 2014;134:2728–36. https://doi.org/10.1038/jid.2014.222.
Nair AB, Jacob S. A simple practice guide for dose conversion between animals and humans. J Basic Clin Pharm. 2016;7(2):27–31. https://doi.org/10.4103/0976-0105.177703.
Nugroho AE, Ikawati Z, Sardjiman Maeyama K. Effects of benzylidenecyclopentanone analogues of curcumin on histamine release from mast cells. Biol Pharm Bull. 2009;32(5):842–9. https://doi.org/10.1248/bpb.32.842.
Otsuka A, Kabashima K. Mast cells and basophils in cutaneous immune responses. Allergy. 2015;70:131–40. https://doi.org/10.1111/all.12526.
Patel SS, Acharya A, Ray RS, Agrawal R, Raghuwanshi R, Jain P. Cellular and molecular mechanisms of curcumin in prevention and treatment of disease. Crit Rev Food Sci Nutr. 2020;60:887–939. https://doi.org/10.1080/10408398.2018.1552244.
Pundir P, Liu R, Vasavda C, Serhan N, Limjunyawong N, Yee R, Zhan Y, Dong X, Wu X, Zhang Y, Snyder SH, Gaudenzio N, Vidal JE, Dong X. A connective tissue mast-cell-specific receptor detects bacterial quorum-sensing molecules and mediates antibacterial immunity. Cell Host Microbe. 2019;26:114-122.e8. https://doi.org/10.1016/j.chom.2019.06.003.
Salehi B, Stojanović-Radić Z, Matejić J, Sharifi-Rad M, Anil Kumar NV, Martins N, Sharifi-Rad J. The therapeutic potential of curcumin: a review of clinical trials. Eur J Med Chem. 2018;163:527–45. https://doi.org/10.1016/j.ejmech.2018.12.016.
Schemann M, Kugler EM, Buhner S, Eastwood C, Donovan J, Jiang W, Grundy D. The mast cell degranulator compound 48/80 directly activates neurons. PLoS ONE. 2012;7(12):e52104. https://doi.org/10.1371/journal.pone.0052104.
Silvestre MC, Sato MN, Reis VMSD. Innate immunity and effector and regulatory mechanisms involved in allergic contact dermatitis. An Bras Dermatol. 2018;93:242–50. https://doi.org/10.1590/abd1806-4841.20186340.
Steinhoff M, Buddenkotte J, Lerner EA. Role of mast cells and basophils in pruritus. Immunol Rev. 2018;282:248–64. https://doi.org/10.1111/imr.12635.
Tatemoto K, Nozaki Y, Tsuda R, Kaneko S, Tomura K, Furuno M, Ogasawara H, Edamura K, Takagi H, Iwamura H, Noguchi M, Naito T. Endogenous protein and enzyme fragments induce immunoglobulin E-independent activation of mast cells via a G protein-coupled receptor, MRGPRX2. Scand J Immunol. 2018;87:e12655. https://doi.org/10.1111/sji.12655.
Thapaliya M, Chompunud Na Ayudhya C, Amponnawarat A, Roy S, Ali H. Mast cell-specific MRGPRX2: a key modulator of neuro-immune interaction in allergic diseases. Curr Allergy Asthma Rep. 2021;21:3. https://doi.org/10.1007/s11882-020-00979-5.
Trinh HT, Bae EA, Lee JJ, Kim DH. Inhibitory effects of curcuminoids on passive cutaneous anaphylaxis reaction and scratching behavior in mice. Arch Pharm Res. 2019;32:1783–7. https://doi.org/10.1007/s12272-009-2217-7.
Tsuda T. Curcumin as a functional food-derived factor: degradation products, metabolites, bioactivity, and future perspectives. Food Funct. 2018;9(2):705–14. https://doi.org/10.1039/c7fo01242j.
Uddin SJ, Hasan MF, Afroz M, Sarker DK, Rouf R, Islam MT, Shilpi JA, Mubarak MS. Curcumin and its multi-target function against pain and inflammation: an update of pre-clinical data. Curr Drug Targets. 2021;22(6):656–71. https://doi.org/10.2174/1389450121666200925150022.
Vaughn AR, Branum A, Sivamani RK. Effects of turmeric (curcuma longa) on skin health: a systematic review of the clinical evidence. Phytother Res. 2016;30:1243–64. https://doi.org/10.1002/ptr.5640.
Vollono L, Falconi M, Gaziano R, Iacovelli F, Dika E, Terracciano C, Bianchi L, Campione E. Potential of curcumin in skin disorders. Nutrients. 2019;11:2169. https://doi.org/10.3390/nu11092169.
Wang X, Rettel M, Krijgsveld J, Feyerabend TB, Rodewald HR. Human mast cell proteome reveals unique lineage, putative functions, and structural basis for cell ablation. Immunity. 2020;52(2):404-416.e5. https://doi.org/10.1016/j.immuni.2020.01.012.
Weber FC, Németh T, Csepregi JZ, Dudeck A, Roers A, Ozsvári B, Oswald E, Puskás LG, Jakob T, Mócsai A, Martin SF. Neutrophils are required for both the sensitization and elicitation phase of contact hypersensitivity. J Exp Med. 2015;212:15–22. https://doi.org/10.1084/jem.20130062.
Ye F, Jiang Y, Zong Y, Zhang J, Zhu C, Yang Y, Tang Z. PLC-IP3-ORAI pathway participates in the activation of the MRGPRB2 receptor in mouse peritoneal mast cells. Immunol Lett. 2022;2022(248):37–44. https://doi.org/10.1016/j.imlet.2022.06.006.
Zhao J, Munanairi A, Liu XY, Zhang J, Hu L, Hu M, Bu D, Liu L, Xie Z, Kim BS, Yang Y, Chen ZF. PAR2 mediates Itch via TRPV3 signaling in keratinocytes. J Invest Dermatol. 2020;140(8):1524–32. https://doi.org/10.1016/j.jid.2020.01.012.
Zhu Y, Pan WH, Wang XR, Liu Y, Chen M, Xu XG, Liao WQ, Hu JH. Tryptase and protease-activated receptor-2 stimulate scratching behavior in a murine model of ovalbumin-induced atopic-like dermatitis. Int Immunopharmacol. 2015;28(1):507–12. https://doi.org/10.1016/j.intimp.2015.04.047.
Acknowledgements
The authors thank Prof. Dong in Johns Hopkins for kindly providing the MrgprB2−/−, MrgprB2-Cre and lsl-Tdtomato animals.
Funding
This work was supported by the Project of National Natural Science Foundation of China (No. 31771163) and the key project of science and technology development plan of traditional Chinese medicine in Jiangsu Province (No. ZD202001).
Author information
Authors and Affiliations
Contributions
ZT: designed and wrote the paper, YJ, YZ and YD: performed experiments, analyzed the data, and wrote part of the paper. All authors read and approved the final manuscript. YJ, YZ and YD: made equal contributions to this work.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare no conflicts of interest.
Additional information
Responsible Editor: Bernhard Gibbs.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Jiang, Y., Zong, Y., Du, Y. et al. Curcumin inhibits the pruritus in mice through mast cell MrgprB2 receptor. Inflamm. Res. 72, 933–945 (2023). https://doi.org/10.1007/s00011-023-01724-0
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00011-023-01724-0