Browse > Article
http://dx.doi.org/10.4062/biomolther.2019.160

FFA2 Activation Ameliorates 2,4-Dinitrochlorobenzene-Induced Atopic Dermatitis in Mice  

Kang, Jisoo (Laboratory of Pharmacology, Department of Pharmacy, College of Pharmacy, Pusan National University)
Im, Dong-Soon (Laboratory of Pharmacology, Department of Pharmacy, College of Pharmacy, Pusan National University)
Publication Information
Biomolecules & Therapeutics / v.28, no.3, 2020 , pp. 267-271 More about this Journal
Abstract
Gut microbiota produce dietary metabolites such as short-chain fatty acids, which exhibit anti-inflammatory effects. Free fatty acid receptor 2 (FFA2, formerly known as GPR43) is a specific receptor for short-chain fatty acids, such as acetate that regulates inflammatory responses. However, the therapeutic potential of FFA2 agonists for treatment of atopic dermatitis has not been investigated. We investigated the efficacy of the FFA2 agonist, 4-chloro-α-(1-methylethyl)-N-2-thiazoylylbenzeneacetanilide (4-CMTB), for treatment of atopic dermatitis induced by 2,4-dinitrochlorobenzene (DNCB). Long-term application of DNCB to the ears of mice resulted in significantly increased IgE in the serum, and induced atopic dermatitis-like skin lesions, characterized by mast cell accumulation and skin tissue hypertrophy. Treatment with 4-CMTB (10 mg/kg, i.p.) significantly suppressed DNCB-induced changes in IgE levels, ear skin hypertrophy, and mast cell accumulation. Treatment with 4-CMTB reduced DNCB-induced increases in Th2 cytokine (IL-4 and IL-13) levels in the ears, but did not alter Th1 or Th17 cytokine (IFN-γ and IL-17) levels. Furthermore, 4-CMTB blocked DNCB-induced lymph node enlargement. In conclusion, activation of FFA2 ameliorated DNCB-induced atopic dermatitis, which suggested that FFA2 is a therapeutic target for atopic dermatitis.
Keywords
Atopy; Dermatitis; Free fatty acid receptor 2; FFA2; Short chain fatty acids;
Citations & Related Records
Times Cited By KSCI : 7  (Citation Analysis)
연도 인용수 순위
1 Davidson, W. F., Leung, D. Y. M., Beck, L. A., Berin, C. M., Boguniewicz, M., Busse, W. W., Chatila, T. A., Geha, R. S., Gern, J. E., Guttman-Yassky, E., Irvine, A. D., Kim, B. S., Kong, H. H., Lack, G., Nadeau, K. C., Schwaninger, J., Simpson, A., Simpson, E. L., Spergel, J. M., Togias, A., Wahn, U., Wood, R. A., Woodfolk, J. A., Ziegler, S. F. and Plaut, M. (2019) Report from the National Institute of Allergy and Infectious Diseases workshop on "Atopic dermatitis and the atopic march: mechanisms and interventions". J. Allergy Clin. Immunol. 143, 894-913.   DOI
2 Huang, J., Su, M., Lee, B. K., Kim, M. J., Jung, J. H. and Im, D. S. (2018) Suppressive effect of 4-hydroxy-2-(4-hydroxyphenethyl) isoindoline-1,3-dione on ovalbumin-induced allergic asthma. Biomol. Ther. (Seoul) 26, 539-545.   DOI
3 Kim, J. Y., Jeong, M. S., Park, M. K., Lee, M. K. and Seo, S. J. (2014) Time-dependent progression from the acute to chronic phases in atopic dermatitis induced by epicutaneous allergen stimulation in NC/Nga mice. Exp. Dermatol. 23, 53-57.   DOI
4 Koga, C., Kabashima, K., Shiraishi, N., Kobayashi, M. and Tokura, Y. (2008) Possible pathogenic role of Th17 cells for atopic dermatitis. J. Invest. Dermatol. 128, 2625-2630.   DOI
5 Le Poul, E., Loison, C., Struyf, S., Springael, J. Y., Lannoy, V., Decobecq, M. E., Brezillon, S., Dupriez, V., Vassart, G., Van Damme, J., Parmentier, M. and Detheux, M. (2003) Functional characterization of human receptors for short chain fatty acids and their role in polymorphonuclear cells activation. J. Biol. Chem. 278, 25481-25489.   DOI
6 Lee, J. M., Park, S. J. and Im, D. S. (2017) Calcium signaling of lysophosphatidylethanolamine through LPA1 in human SH-SY5Y neuroblastoma cells. Biomol. Ther. (Seoul) 25, 194-201.   DOI
7 Lee, S. Y., Lee, E., Park, Y. M. and Hong, S. J. (2018) Microbiome in the gut-skin axis in atopic dermatitis. Allergy Asthma Immunol. Res. 10, 354-362.   DOI
8 Maslowski, K. M., Vieira, A. T., Ng, A., Kranich, J., Sierro, F., Yu, D., Schilter, H. C., Rolph, M. S., Mackay, F., Artis, D., Xavier, R. J., Teixeira, M. M. and Mackay, C. R. (2009) Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature 461, 1282-1286.   DOI
9 Lee, T., Schwandner, R., Swaminath, G., Weiszmann, J., Cardozo, M., Greenberg, J., Jaeckel, P., Ge, H., Wang, Y., Jiao, X., Liu, J., Kayser, F., Tian, H. and Li, Y. (2008) Identification and functional characterization of allosteric agonists for the G protein-coupled receptor FFA2. Mol. Pharmacol. 74, 1599-1609.   DOI
10 Leung, D. Y. and Guttman-Yassky, E. (2017) Assessing the current treatment of atopic dermatitis: unmet needs. J. Allergy Clin. Immunol. 139, S47-S48.   DOI
11 Miyamoto, J., Kasubuchi, M., Nakajima, A. and Kimura, I. (2017) Antiinflammatory and insulin-sensitizing effects of free fatty acid receptors. Handb. Exp. Pharmacol. 236, 221-231.
12 Muraro, A., Lemanske, R. F., Jr., Hellings, P. W., Akdis, C. A., Bieber, T., Casale, T. B., Jutel, M., Ong, P. Y., Poulsen, L. K., Schmid-Grendelmeier, P., Simon, H. U., Seys, S. F. and Agache, I. (2016) Precision medicine in patients with allergic diseases: airway diseases and atopic dermatitis-PRACTALL document of the European Academy of Allergy and Clinical Immunology and the American Academy of Allergy, Asthma & Immunology. J. Allergy Clin. Immunol. 137, 1347-1358.   DOI
13 Nilsson, N. E., Kotarsky, K., Owman, C. and Olde, B. (2003) Identification of a free fatty acid receptor, FFA2R, expressed on leukocytes and activated by short-chain fatty acids. Biochem. Biophys. Res. Commun. 303, 1047-1052.   DOI
14 Park, S. J. and Im, D. S. (2019a) Blockage of sphingosine-1-phosphate receptor 2 attenuates allergic asthma in mice. Br. J. Pharmacol. 176, 938-949.   DOI
15 Theiler, A., Barnthaler, T., Platzer, W., Richtig, G., Peinhaupt, M., Rittchen, S., Kargl, J., Ulven, T., Marsh, L. M., Marsche, G., Schuligoi, R., Sturm, E. M. and Heinemann, A. (2019) Butyrate ameliorates allergic airway inflammation by limiting eosinophil trafficking and survival. J. Allergy Clin. Immunol. 144, 764-776.   DOI
16 Park, S. J. and Im, D. S. (2019b) Deficiency of sphingosine-1-phosphate receptor 2 (S1P2) attenuates bleomycin-induced pulmonary fibrosis. Biomol. Ther. (Seoul) 27, 318-326.   DOI
17 Schofield, Z. V., Croker, D., Robertson, A. A. B., Massey, N. L., Donovan, C., Tee, E., Edwards, D., Woodruff, T. M., Halai, R., Hansbro, P. M. and Cooper, M. A. (2018) Characterisation of small molecule ligands 4CMTB and 2CTAP as modulators of human FFA2 receptor signalling. Sci. Rep. 8, 17819.   DOI
18 Smith, N. J., Ward, R. J., Stoddart, L. A., Hudson, B. D., Kostenis, E., Ulven, T., Morris, J. C., Trankle, C., Tikhonova, I. G., Adams, D. R. and Milligan, G. (2011) Extracellular loop 2 of the free fatty acid receptor 2 mediates allosterism of a phenylacetamide ago-allosteric modulator. Mol. Pharmacol. 80, 163-173.   DOI
19 Sun, M., Wu, W., Liu, Z. and Cong, Y. (2017) Microbiota metabolite short chain fatty acids, GPCR, and inflammatory bowel diseases. J. Gastroenterol. 52, 1-8.   DOI
20 Tan, J. K., McKenzie, C., Marino, E., Macia, L. and Mackay, C. R. (2017) Metabolite-sensing G protein-coupled receptors-facilitators of diet-related immune regulation. Annu. Rev. Immunol. 35, 371-402.   DOI
21 Trompette, A., Gollwitzer, E. S., Yadava, K., Sichelstiel, A. K., Sprenger, N., Ngom-Bru, C., Blanchard, C., Junt, T., Nicod, L. P., Harris, N. L. and Marsland, B. J. (2014) Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis. Nat. Med. 20, 159-166.   DOI
22 Ulven, T. (2012) Short-chain free fatty acid receptors FFA2/GPR43 and FFA3/GPR41 as new potential therapeutic targets. Front. Endocrinol. (Lausanne) 3, 111.   DOI
23 Arrieta, M. C., Stiemsma, L. T., Dimitriu, P. A., Thorson, L., Russell, S., Yurist-Doutsch, S., Kuzeljevic, B., Gold, M. J., Britton, H. M., Lefebvre, D. L., Subbarao, P., Mandhane, P., Becker, A., McNagny, K. M., Sears, M. R., Kollmann, T., Investigators, C. S., Mohn, W. W., Turvey, S. E. and Finlay, B. B. (2015) Early infancy microbial and metabolic alterations affect risk of childhood asthma. Sci. Transl. Med. 7, 307ra152.   DOI
24 Brown, A. J., Goldsworthy, S. M., Barnes, A. A., Eilert, M. M., Tcheang, L., Daniels, D., Muir, A. I., Wigglesworth, M. J., Kinghorn, I., Fraser, N. J., Pike, N. B., Strum, J. C., Steplewski, K. M., Murdock, P. R., Holder, J. C., Marshall, F. H., Szekeres, P. G., Wilson, S., Ignar, D. M., Foord, S. M., Wise, A. and Dowell, S. J. (2003) The Orphan G protein-coupled receptors GPR41 and GPR43 are activated by propionate and other short chain carboxylic acids. J. Biol. Chem. 278, 11312-11319.   DOI