Postexercise Inflammasome Activation and IL-1β Production Mitigated by Flavonoid Supplementation in Cyclists

in International Journal of Sport Nutrition and Exercise Metabolism
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  • 1 Appalachian State University
  • 2 NC State University
  • 3 University of Ferrara
  • 4 Kyung Hee University
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Inflammasomes are multiprotein signaling platforms of the innate immune system that detect markers of physiological stress and promote the maturation of caspase-1 and interleukin 1 beta (IL-1β), IL-18, and gasdermin D. This randomized, cross-over trial investigated the influence of 2-week mixed flavonoid (FLAV) versus placebo (PL) supplementation on inflammasome activation and IL-1β and IL-18 production after 75-km cycling in 22 cyclists (42 ± 1.7 years). Blood samples were collected before and after the 2-week supplementation, and then 0 hr, 1.5 hr, and 21 hr postexercise (176 ± 5.4 min, 73.4 ± 2.0 %VO2max). The supplement (678 mg FLAVs) included quercetin, green tea catechins, and bilberry anthocyanins. The pattern of change in the plasma levels of the inflammasome adaptor oligomer ASC (apoptosis-associated speck-like protein containing caspase recruitment domain) was different between the FLAV and PL trials, with the FLAV ASC levels 52% lower (Cohen’s d = 1.06) than PL immediately following 75-km cycling (interaction effect, p = .012). The plasma IL-1β levels in FLAV were significantly lower than PL (23–42%; Cohen’s d = 0.293–0.644) throughout 21 hr of recovery (interaction effect, p = .004). The change in plasma gasdermin D levels were lower immediately postexercise in FLAV versus PL (15% contrast, p = .023; Cohen’s d = 0.450). The patterns of change in plasma IL-18 and IL-37 did not differ between the FLAV and PL trials (interaction effects, p = .388, .716, respectively). These data indicate that 2-week FLAV ingestion mitigated inflammasome activation, with a corresponding decrease in IL-1β release in cyclists after a 75-km cycling time trial. The data from this study support the strategy of ingesting high amounts of FLAV to mitigate postexercise inflammation.

Nieman, Hoyle, and Simonson are with the Human Performance Laboratory, Appalachian State University, North Carolina Research Campus, Kannapolis, NC, USA. Ferrara, Pecorelli, Woodby, and Valacchi are with the Department of Animal Sciences, Plants for Human Health Institute, NC State University, Kannapolis, NC, USA. Ferrara and Valacchi are with the Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy. Valacchi is with the Department of Food and Nutrition, Kyung Hee University, Seoul, South Korea.

Nieman and Valacchi (niemandc@appstate.edu; gvalacc@ncsu.edu) are corresponding authors.
  • Abkenar, K., Rahmani-Nia, F., & Lombardi, G. (2019). The effects of acute and chronic aerobic activity on the signaling pathway of the inflammasome NLRP3 complex in young men. Medicina, 55(4), 105. PubMed ID: 30991661 doi:10.3390/medicina55040105

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Afonina, I.S., Zhong, Z., Karin, M., & Beyaert, R. (2017). Limiting inflammation-the negative regulation of NF-κB and the NLRP3 inflammasome. Nature Immunology, 18(8), 861869. PubMed ID: 28722711 doi:10.1038/ni.3772

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Ahmed, M.E., Iyer, S., Thangavel, R., Kempuraj, D., Selvakumar, G.P., Raikwar, S.P., … Zaheer, A. (2017). Co-localization of glia maturation factor with NLRP3 Inflammasome and autophagosome markers in human Alzheimer’s disease brain. Journal of Alzheimer’s Disease, 60(3), 11431160. PubMed ID: 28984607 doi:10.3233/JAD-170634

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Albornoz, E.A., Woodruff, T.M., & Gordon, R. (2018). Inflammasomes in CNS diseases. Experientia Supplemntum, 108, 4160. PubMed ID: 30536167 doi:10.1007/978-3-319-89390-7_3

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Baroja-Mazo, A., Martín-Sánchez, F., & Gomez, A. (2014). The NLRP3 inflammasome is released as a particulate danger signal that amplifies the inflammatory response. Nature Immunology, 15(8), 738748. PubMed ID: 24952504 doi:10.1038/ni.2919

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Bertinaria, M., Gastaldi, S., Marini, E., & Giorgis, M. (2019). Development of covalent NLRP3 inflammasome inhibitors: Chemistry and biological activity. Archives of Biochemistry and Biophysics, 670, 116139. PubMed ID: 30448387 doi:10.1016/j.abb.2018.11.013

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Bocci, V., & Valacchi, G. (2015). Nrf2 activation as target to implement therapeutic treatments. Frontiers in Chemistry, 3, 4. PubMed ID: 25699252 doi:10.3389/fchem.2015.00004

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Butts, B., Butler, J., Dunbar, S.B., Corwin, E., & Gary, R.A. (2018). Effects of exercise on ASC methylation and IL-1 cytokines in heart failure. Medicine and Science in Sports and Exercise, 50(9), 17571766. PubMed ID: 29683921 doi:10.1249/MSS.0000000000001641

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Cavalli, G., Ballak, D., Justice, J., Boyle, K., Dalessandro, A., Joosten, L., & Dinarello, C. (2017). Interleukin 37 reverses the metabolic cost of inflammation, increases oxidative respiration and improves exercise tolerance. Proceedings of the National Academies of Sciences of the United States of America, 114(9), 23132318. PubMed ID: 28193888 doi:10.1073/pnas.1619011114

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Chei, S., Oh, H., Song, J., Seo, Y., Lee, K., Kee, K., & Lee, B. (2020). Spirulina maxima extract prevents activation of the NLRP3 inflammasome by inhibiting ERK signaling. Scientific Reports, 10(1), 2075. PubMed ID: 32034213 doi:10.1038/s41598-020-58896-6

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Di Gesso, J.L., Kerr, J.S., Zhang, Q., Raheem, S., Yalamanchili, S.K., O’Hagan, D., …O’Connell, M.A. (2015). Flavonoid metabolites reduce tumor necrosis factor-α secretion to a greater extent than their precursor compounds in human THP-1 monocytes. Molecular Nutrition & Food Research, 59(6), 11431154. PubMed ID: 25801720 doi:10.1002/mnfr.201400799

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Ferrara, F., Pambianchi, E., Pecorelli, A., Woodby, B., Messano, N., Therrien, J. P., … Valacchi, G. (2019). Redox regulation of cutaneous inflammasome by ozone exposure. Free Radical Biology & Medicine, 152, 561570. PubMed ID: 31778733 doi:10.1016/j.freeradbiomed.2019.11.031

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Gorka, O., Neuwirt, E., & Grob, O. (2019). Walking over the inflammasome. Natural Chemical Biology, 15(6), 552553. PubMed ID: 31086328 doi:10.1038/s41589-019-0292-8

    • Crossref
    • Search Google Scholar
    • Export Citation
  • He, Y., Hara, H., & Núńez, G. (2016). Mechanism and regulation of NLRP3 inflammasome activation. Trends in Biochemical Sciences, 41(12), 10121021. PubMed ID: 27669650 doi:10.1016/j.tibs.2016.09.002

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Jhang, J., Lin, J., & Yen, G. (2018). Beneficial properties of phytochemicals on NLRP3 inflammasome-mediated gout and complication. Journal of Agricultural and Food Chemistry, 66(4), 765772. PubMed ID: 29293001 doi:10.1021/acs.jafc.7b05113

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Jo, E., Kim, J., Shin, D., & Sasakawa, C. (2016). Molecular mechanisms regulating NLRP3 inflammasome activation. Cellular and Molecular Immunology, 13(2), 148159. PubMed ID: 26549800 doi:10.1038/cmi.2015.95

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Kalt, W., Cassidy, A., Howard, L.R., Krikorian, R., Stull, A.J., Tremblay, F., & Zamora-Ros, R. (2020). Recent research on the health benefits of blueberries and their anthocyanins. Advances in Nutrition, 11(2), 224236. PubMed ID: 31329250 doi:10.1093/advances/nmz065

    • Search Google Scholar
    • Export Citation
  • Kay, C.D., Pereira-Caro, G., Ludwig, I.A., Clifford, M.N., & Crozier, A. (2017). Anthocyanins and flavanones are more bioavailable than previously perceived: A review of recent evidence. Annual Review of Food Science and Technology, 28, 155180. PubMed ID: 28125348 doi:10.1146/annurev-food-030216-025636

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Kerr, N., García-Contreras, M., Abbassi, S., Mejias, N. H., Desousa, B. R., Ricordi, C., … de Rivero Vaccari, J. P. (2018). Inflammasome proteins in serum and serum-derived extracellular vesicles as biomarkers of stroke. Frontiers in molecular neuroscience, 11, 309. PubMed ID: 30233311 doi:10.3389/fnmol.2018.00309

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Krzemiński, K., Buraczewska, M., Miśkiewicz, Z., Dąbrowski, J., Steczkowska, M., Kozacz, A., & Ziemba, A. (2016). Effect of ultra-endurance exercise on left ventricular performance and plasma cytokines in healthy trained men. Biology of Sport, 33(1), 6369. PubMed ID: 26985136 doi:10.5604/20831862.1189767

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Li, H., Miao, W., Ma, J., Xv, Z., Bo, H., Li, J., … Ji, LL. (2016). Acute exercise-induced mitochondrial stress triggers an inflammatory response in the myocardium via NLRP3 inflammasome activation with mitophagy. Oxidative Medicine and Cellular Longevity, 2016, 1987149. PubMed ID: 26770647 doi:10.1155/2016/1987149

    • Search Google Scholar
    • Export Citation
  • Lugrin, J., & Martinon, F. (2017). Detection of ASC oligomerization by Western blotting. Bio-Protocol, 7(10), e2292. PubMed ID: 29085861 doi:10.21769/BioProtoc.2292

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Mathur, A., Hayward, J.A., & Man, S.M. (2017). Molecular mechanisms of inflammasome signaling. Journal of Leukocyte Biology, 103(2), 233257. PubMed ID: 28855232 doi:10.1189/jlb.3MR0617-250R

    • Search Google Scholar
    • Export Citation
  • Nakajima, K., Takeoka, M., Mori, M., Hashimoto, S., Sakurai, A., Nose, H., … Taniguchi, S. (2010). Exercise effects on methylation of ASC gene. International Journal of Sports Medicine, 31(9), 671675. PubMed ID: 20200803 doi:10.1055/s-0029-1246140

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Nehlsen-Cannarella, S.L., Fagoaga, O.R., Nieman, D.C., Henson, D.A., Butterworth, D.E., Schmitt, R.L., & Davis, J.M. (1997). Carbohydrate and the cytokine response to 2.5 h of running. Journal of Applied Physiology, 82(5), 16621667. PubMed ID: 9134917 doi:10.1152/jappl.1997.82.5.1662

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Neumayr, G., Ludwiczek, O., Hoertnagl, H., Pfister, R., Mitterbauer, G., Moschen, A., & Tilg, H. (2005). The impact of prolonged strenuous endurance exercise on interleukin 18 and interleukin 18 binding protein in recreational cyclists. International Journal of Sports Medicine, 26(10), 836840. PubMed ID: 16320167 doi:10.1055/s-2005-837466

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Nieman, D.C., Henson, D.A., Smith, L.L., Utter, A.C., Vinci, D.M., Davis, J.M., … Shute, M. (2001). Cytokine changes after a marathon race. Journal of Applied Physiology, 91(1), 109114. PubMed ID: 11408420 doi:10.1152/jappl.2001.91.1.109

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Nieman, D.C., Kay, C.D., Rathore, A.S., Grace, M.H., Strauch, R.C., Stephan, E.H., … Lila, M.A. (2018). Increased plasma levels of gut-derived phenolics linked to walking and running following 2-weeks flavonoid supplementation. Nutrients, 10(11), 1718. PubMed ID: 30423955 doi:10.3390/nu10111718

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Nieman, D.C., Konrad, M., Henson, D.A., Kennerly, K., Shanely, R.A., & Wallner-Liebmann, S.J. (2012). Variance in the acute inflammatory response to prolonged cycling is linked to exercise intensity. Journal of Interferon and Cytokine Research, 32(1), 1217. PubMed ID: 21916608 doi:10.1089/jir.2011.0038

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Nieman, D.C., Lila, M.A., & Gillitt, N.D. (2019). Immunometabolism: A multi-omics approach to interpreting the influence of exercise and diet on the immune system. Annual Review of Food Science and Technology, 10, 341363. PubMed ID: 30633566 doi:10.1146/annurev-food-032818-121316

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Nieman, D.C., Ramamoorthy, S., Kay, C.D., Goodman, C.L., Capps, C.R., Shue, Z.L., … Lila, M.A. (2017). Influence of ingesting a flavonoid-rich supplement on the metabolome and concentration of urine phenolics in overweight/obese women. Journal of Proteome Research, 16(8), 29242935. PubMed ID: 28631923 doi:10.1021/acs.jproteome.7b00196

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Nieman, D.C., Valacchi, G., Wentz, L.M., Ferrara, F., Woodby, B., Sakaguchi, C.A., & Simonson, A. (2020). Mixed flavonoid supplementation attenuates post-exercise plasma levels of protein carbonyls and 4-hydroxynonenal protein adduct levels in endurance athletes. International Journal of Sport Nutrition and Exercise Metabolism, 30, 112119.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Nieman, D.C., & Wentz, L.M. (2019). The compelling link between physical activity and the body’s defense system. Journal of Sport & Health Science, 8(3), 201217.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Nishida, Y., Hara, M., Higaki, Y., Taguchi, N., Nakamura, K., Nanri, H., … Tanaka, K. (2019). Habitual light-intensity physical activity and ASC methylation in a middle-aged population. International Journal of Sports Medicine, 40(10), 670677. PubMed ID: 31342477 doi:10.1055/a-0965-1374

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Peake, J.M., Della Gatta, P., Suzuki, K., & Nieman, D.C. (2015). Cytokine expression and secretion by skeletal muscle cells: Regulatory mechanisms and exercise effects. Exercise Immunology Review, 21, 825. PubMed ID: 25826432

    • Search Google Scholar
    • Export Citation
  • Pellegrini, C., Fornai, M., Antonioli, L., Blandizzi, C., & Calderone, V. (2019). Phytochemicals as novel therapeutic strategies for NLRP3 inflammasome-related neurological, metabolic, and inflammatory diseases. International Journal of Molecular Sciences, 20(12), 2876. PubMed ID: 31200447 doi:10.3390/ijms20122876

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Rudloff, I., Ung, H.K., Dowling, J.K., Mansell, A., D’Andrea, L., Ellisdon, A.M., … Nold, M.F. (2020). Parsing the IL-37-mediated suppression of inflammasome function. Cells, 9(1), 178. PubMed ID: 31936823 doi:10.3390/cells9010178

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Sebastian, R.S., Wilkinson Enns, C., Goldman, J.D., Martin, C.L., Steinfeldt, L.C., Murayi, T., & Moshfegh, A.J. (2015). A new database facilitates characterization of flavonoid intake, sources, and positive associations with diet quality among US adults. Journal of Nutrition, 145(6), 12391248. PubMed ID: 25948787 doi:10.3945/jn.115.213025

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Shao, B., Xu, Z., Han, B., Su, D., & Liu, C. (2015). NLRP3 inflammasome and its inhibitors: a review. Frontiers in Pharmacology, 6, 262. PubMed ID: 26594174 doi:10.3389/fphar.2015.00262

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Sivandzade, F., Prasad, S., Bhalerao, A., & Cucullo, L. (2019). NRF2 and NF-κB interplay in cerebrovascular and neurodegenerative disorders: Molecular mechanisms and possible therapeutic approaches. Redox Biology, 21, 101059. PubMed ID: 30576920 doi:10.1016/j.redox.2018.11.017

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Sugama, K., Suzuki, K., Yoshitani, K., Shiraishi, K., & Kometani, T. (2013). Urinary excretion of cytokines versus their plasma levels after endurance exercise. Exercise Immunology Review, 19, 2948. PubMed ID: 23977718

    • Search Google Scholar
    • Export Citation
  • Sutterwala, F.S., Haasken, S., & Cassel, S. (2014). Mechanism of NLRP3 Inflammasome activation. Annals of the New York Academy of Sciences, 1319(1), 8295. PubMed ID: 24840700 doi:10.1111/nyas.12458

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Suzuki, K., Nakaji, S., & Yamada, M. (2003). Impact of a competitive marathon race on systemic cytokine and neutrophil responses. Medicine and Science in Sports and Exercise 35(2), 348355. PubMed ID: 12569227 doi:10.1249/01.MSS.0000048861.57899.04

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Swanson, K.V., Deng, M., & Ting, J.P. (2019). The NLRP3 inflammasome: Molecular activation and regulation to therapeutics. Nature Reviews in Immunology, 19(8), 477489. PubMed ID: 31036962 doi:10.1038/s41577-019-0165-0

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Valacchi, G., Virgili, F., Cervellati, C., & Pecorelli, A. (2018). OxInflammation: From subclinical condition to pathological biomarker. Frontiers in Physiology, 9, 858. PubMed ID: 30038581 doi:10.3389/fphys.2018.00858

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Wang, G., Song, X., Zhao, L., Li, Z., & Liu, B. (2018). Resveratrol prevents diabetic cardiomyopathy by increasing Nrf2 expression and transcriptional activity. Biomedical Research International, 2018, 2150218. PubMed ID: 29721501 doi:10.1155/2018/2150218

    • Search Google Scholar
    • Export Citation
  • Wang, X., Eagon, W., & Lee, J. (2020). Orchestration of human macrophage NLRP3 inflammasome activation by Staphylococcus aureus extracellular vesicles. Proceedings of the National Academies of Sciences, 117(6), 31743184. PubMed ID: 31988111 doi:10.1073/pnas.1915829117

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Williamson, G., Kay, C.D., & Crozier, A. (2018). The bioavailability, transport, and bioactivity of dietary flavonoids: A review from a historical perspective. Comprehensive Reviews in Food Science and Food Safety, 17(5), 10541112.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Yi, S. (2018). Role of inflammasomes in inflammatory autoimmune rheumatic diseases. The Korean Journal of Physiology and Pharmacology, 22(1), 115. PubMed ID: 29302207 doi:10.4196/kjpp.2018.22.1.1

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Zhang, X., Xu, A., Lv, J., Zhang, Q., Ran, Y., Wei, C., & Wu, J. (2020). Development of small molecule inhibitors targeting NLRP3 inflammasome pathway for inflammatory diseases. European Journal of Medicinal Chemistry, 185, 111822. PubMed ID: 31699536 doi:10.1016/j.ejmech.2019.111822

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Zhou, R., Yazdi, A.S., Menu, P., & Tschopp, J. (2011). A role for mitochondria in NLRP3 inflammasome activation. Nature, 469(7329), 221225. PubMed ID: 21124315 doi:10.1038/nature09663

    • Crossref
    • Search Google Scholar
    • Export Citation
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