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Phenylalanine diminishes M1 macrophage inflammation

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Abstract

Emerging evidence suggests that amino acids dictate the effector functions of immune cells; however, whether and how phenylalanine (Phe) orchestrates the polarization of macrophages is not understood. Here, we determined that Phe attenuated lipopolysaccharide (LPS) and P. multocida serotype A strain CQ2 (PmCQ2) infection-induced inflammation in vivo. Furthermore, we demonstrated that Phe inhibited the production of interleukin (IL)-1β and tumor necrosis factor (TNF)-α in proinflammatory (M1) macrophages. Phe reprogrammed the transcriptomic and metabolic profiles and enhanced oxidative phosphorylation in M1 macrophages, which reduced the activation of caspase-1. Notably, the valine-succinyl-CoA axis played a critical role in Phe-mediated inhibition of IL-1β production in M1 macrophages. Taken together, our findings suggest that manipulating the valine-succinyl-CoA axis provides a potential target for preventing and/or treating macrophage-related diseases.

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References

  • Baasch, S., Giansanti, P., Kolter, J., Riedl, A., Forde, A.J., Runge, S., Zenke, S., Elling, R., Halenius, A., Brabletz, S., et al. (2021). Cytomegalovirus subverts macrophage identity. Cell 184, 3774–3793.e25.

    PubMed  CAS  Google Scholar 

  • Buck, M.D., Sowell, R.T., Kaech, S.M., and Pearce, E.L. (2017). Metabolic instruction of immunity. Cell 169, 570–586.

    PubMed  PubMed Central  CAS  Google Scholar 

  • Chen, S., Xia, Y., He, F., Fu, J., Xin, Z., Deng, B., He, L., Zhou, X., and Ren, W. (2020). Serine supports IL-1β production in macrophages through mTOR signaling. Front Immunol 11, 1866.

    PubMed  PubMed Central  CAS  Google Scholar 

  • Covarrubias, A.J., Aksoylar, H.I., and Horng, T. (2015). Control of macrophage metabolism and activation by mTOR and Akt signaling. Semin Immunol 27, 286–296.

    PubMed  PubMed Central  CAS  Google Scholar 

  • Fu, J., Han, Z., Wu, Z., Xia, Y., Yang, G., Yin, Y., and Ren, W. (2022). GABA regulates IL-1β production in macrophages. Cell Rep 41, 111770.

    PubMed  CAS  Google Scholar 

  • Ge, G., Bai, J., Wang, Q., Liang, X., Tao, H., Chen, H., Wei, M., Niu, J., Yang, H., Xu, Y., et al. (2022). Punicalagin ameliorates collagen-induced arthritis by downregulating M1 macrophage and pyroptosis via NF-kB signaling pathway. Sci China Life Sci 65, 588–603.

    PubMed  CAS  Google Scholar 

  • Geiß, C., Salas, E., Guevara-Coto, J., Régnier-Vigouroux, A., and Mora-Rodríguez, R.A. (2022). Multistability in macrophage activation pathways and metabolic implications. Cells 11, 404.

    PubMed  PubMed Central  Google Scholar 

  • Guo, H., Callaway, J.B., and Ting, J.P.Y. (2015). Inflammasomes: mechanism of action, role in disease, and therapeutics. Nat Med 21, 677–687.

    PubMed  PubMed Central  Google Scholar 

  • He, F., Wu, C., Li, P., Li, N., Zhang, D., Zhu, Q., Ren, W., and Peng, Y. (2018). Functions and signaling pathways of amino acids in intestinal inflammation. Biomed Res Int 2018, 1–13.

    CAS  Google Scholar 

  • He, F., Yin, Z., Wu, C., Xia, Y., Wu, M., Li, P., Zhang, H., Yin, Y., Li, N., Zhu, G., et al. (2019). L-serine lowers the inflammatory responses during pasteurella multocida infection. Infect Immun 87.

  • Hu, X., Li, J., Fu, M., Zhao, X., and Wang, W. (2021). The JAK/STAT signaling pathway: from bench to clinic. Sig Transduct Target Ther 6, 402.

    Google Scholar 

  • Janata, J., Kogekar, N., and Fenton, W.A. (1997). Expression and kinetic characterization of methylmalonyl-CoA mutase from patients with the mut phenotype: evidence for naturally occurring interallelic complementation. Hum Mol Genet 6, 1457–1464.

    PubMed  CAS  Google Scholar 

  • Jha, A.K., Huang, S.C.C., Sergushichev, A., Lampropoulou, V., Ivanova, Y., Loginicheva, E., Chmielewski, K., Stewart, K.M., Ashall, J., Everts, B., et al. (2015). Network integration of parallel metabolic and transcriptional data reveals metabolic modules that regulate macrophage polarization. Immunity 42, 419–430.

    PubMed  CAS  Google Scholar 

  • Ji, L., Zhao, X., Zhang, B., Kang, L., Song, W., Zhao, B., Xie, W., Chen, L., and Hu, X. (2019). Slc6a8 mediated creatine uptake and accumulation reprogram macrophage polarization via regulating cytokine responses. Immunity 51, 272–284.e7.

    PubMed  CAS  Google Scholar 

  • Jiang, Y., Sun, B., Qian, F., Dong, F., Xu, C., Zhong, W., Huang, R., Zhai, Q., Jiang, Y., and Yang, S. (2023). Expression of phenylalanine ammonia lyase as an intracellularly free and extracellularly cell surface-immobilized enzyme on a gut microbe as a live biotherapeutic for phenylketonuria. Sci China Life Sci 66, 127–136.

    PubMed  CAS  Google Scholar 

  • Kanai, Y. (2022). Amino acid transporter LAT1 (SLC7A5) as a molecular target for cancer diagnosis and therapeutics. Pharmacol Ther 230, 107964.

    PubMed  CAS  Google Scholar 

  • Kato, T., Yamazaki, K., Nakajima, M., Date, Y., Kikuchi, J., Hase, K., Ohno, H., and Yamazaki, K. (2018). Oral Administration of Porphyromonas gingivalis Alters the Gut Microbiome and Serum Metabolome. Msphere 3.

  • Kelly, B., and O’Neill, L.A. (2015). Metabolic reprogramming in macrophages and dendritic cells in innate immunity. Cell Res 25, 771–784.

    PubMed  PubMed Central  Google Scholar 

  • Kelly, B., and Pearce, E.L. (2020). Amino assets: how amino acids support immunity. Cell Metab 32, 154–175.

    PubMed  CAS  Google Scholar 

  • Koelwyn, G.J., Corr, E.M., Erbay, E., and Moore, K.J. (2018). Regulation of macrophage immunometabolism in atherosclerosis. Nat Immunol 19, 526–537.

    PubMed  PubMed Central  CAS  Google Scholar 

  • Li, C., Xu, X., Wei, S., Jiang, P., Xue, L., and Wang, J. (2021). Tumor-associated macrophages: potential therapeutic strategies and future prospects in cancer. J Immunother Cancer 9, e001341.

    PubMed  PubMed Central  Google Scholar 

  • Liu, X., Su, Y., Sun, X., Fu, H., Huang, Q., Chen, Q., Mo, X., Lv, M., Kong, Y., Xu, L., et al. (2020). Arsenic trioxide alleviates acute graft-versus-host disease by modulating macrophage polarization. Sci China Life Sci 63, 1744–1754.

    PubMed  CAS  Google Scholar 

  • Locati, M., Curtale, G., and Mantovani, A. (2020). Diversity, mechanisms, and significance of macrophage plasticity. Annu Rev Pathol Mech Dis 15, 123–147.

    CAS  Google Scholar 

  • Murphy, M.P., and O’Neill, L.A.J. (2018). Krebs cycle reimagined: the emerging roles of succinate and itaconate as signal transducers. Cell 174, 780–784.

    PubMed  CAS  Google Scholar 

  • Murray, P.J. (2017). Macrophage polarization. Annu Rev Physiol 79, 541–566.

    PubMed  CAS  Google Scholar 

  • Neinast, M.D., Jang, C., Hui, S., Murashige, D.S., Chu, Q., Morscher, R.J., Li, X., Zhan, L., White, E., Anthony, T.G., et al. (2019). Quantitative analysis of the whole-body metabolic fate of branched-chain amino acids. Cell Metab 29, 417–429.e4.

    PubMed  CAS  Google Scholar 

  • O’Neill, L.A.J., and Artyomov, M.N. (2019). Itaconate: the poster child of metabolic reprogramming in macrophage function. Nat Rev Immunol 19, 273–281.

    PubMed  Google Scholar 

  • Park, J., Chen, Y., Tishkoff, D.X., Peng, C., Tan, M., Dai, L., Xie, Z., Zhang, Y., Zwaans, B.M.M., Skinner, M.E., et al. (2013). SIRT5-mediated lysine desuccinylation impacts diverse metabolic pathways. Mol Cell 50, 919–930.

    PubMed  PubMed Central  CAS  Google Scholar 

  • Peng, H., Wang, Y., and Luo, W. (2020). Multifaceted role of branched-chain amino acid metabolism in cancer. Oncogene 39, 6747–6756.

    PubMed  PubMed Central  CAS  Google Scholar 

  • Płóciennikowska, A., Hromada-Judycka, A., Borzęcka, K., and Kwiatkowska, K. (2015). Co-operation of TLR4 and raft proteins in LPS-induced pro-inflammatory signaling. Cell Mol Life Sci 72, 557–581.

    PubMed  Google Scholar 

  • Schmacke, N.A., O’Duill, F., Gaidt, M.M., Szymanska, I., Kamper, J.M., Schmid-Burgk, J.L., Mädler, S.C., Mackens-Kiani, T., Kozaki, T., Chauhan, D., et al. (2022). IKKβ primes inflammasome formation by recruiting NLRP3 to the trans-Golgi network. Immunity 55, 2271–2284.e7.

    PubMed  PubMed Central  CAS  Google Scholar 

  • Shellhammer, J.P., Morin-Kensicki, E., Matson, J.P., Yin, G.W., Isom, D. G., Campbell, S.L., Mohney, R.P., and Dohlman, H.G. (2017). Amino acid metabolites that regulate G protein signaling during osmotic stress. PloS Genet 13, e1006829.

    PubMed  PubMed Central  Google Scholar 

  • Shen, C., Chen, J.H., Lee, Y., Hassan, M.M., Kim, S.J., Choi, E.Y., Hong, S.T., Park, B.H., and Park, J.H. (2018). mTOR- and SGK-mediated connexin 43 expression participates in lipopolysaccharide-stimulated macrophage migration through the iNOS/Src/FAK axis. J Immunol 201, 2986–2997.

    PubMed  CAS  Google Scholar 

  • Shirai, T., Nazarewicz, R.R., Wallis, B.B., Yanes, R.E., Watanabe, R., Hilhorst, M., Tian, L., Harrison, D.G., Giacomini, J.C., Assimes, T.L., et al. (2016). The glycolytic enzyme PKM2 bridges metabolic and inflammatory dysfunction in coronary artery disease. J Exp Med 213, 337–354.

    PubMed  PubMed Central  CAS  Google Scholar 

  • Swanson, K.V., Deng, M., and Ting, J.P.Y. (2019). The NLRP3 inflammasome: molecular activation and regulation to therapeutics. Nat Rev Immunol 19, 477–489.

    PubMed  PubMed Central  CAS  Google Scholar 

  • Van den Bossche, J., O’Neill, L.A., and Menon, D. (2017). Macrophage immunometabolism: where are we (going)? Trends Immunol 38, 395–406.

    PubMed  CAS  Google Scholar 

  • Wang, B., Chen, T., Li, G., Jia, Y., Wang, J., Xue, L., and Chen, Y. (2019). Dopamine alters lipopolysaccharide-induced nitric oxide production in microglial cells via activation of D1-like receptors. Neurochem Res 44, 947–958.

    PubMed  Google Scholar 

  • Wang, H., Zheng, X., Liu, B., Xia, Y., Xin, Z., Deng, B., He, L., Deng, J., and Ren, W. (2021). Aspartate metabolism facilitates IL-1β production in inflammatory macrophages. Front Immunol 12, 753092.

    PubMed  PubMed Central  CAS  Google Scholar 

  • Wang, J., Wang, Y., Zhang, X., Liu, J., Zhang, Q., Zhao, Y., Peng, J., Feng, Q., Dai, J., Sun, S., et al. (2017a). Gut microbial dysbiosis is associated with altered hepatic functions and serum metabolites in chronic hepatitis B patients. Front Microbiol 8, 2222.

    PubMed  PubMed Central  Google Scholar 

  • Wang, Y., Guo, Y.R., Liu, K., Yin, Z., Liu, R., Xia, Y., Tan, L., Yang, P., Lee, J.H., Li, X.J., et al. (2017b). KAT2A coupled with the α-KGDH complex acts as a histone H3 succinyltransferase. Nature 552, 273–277.

    PubMed  PubMed Central  CAS  Google Scholar 

  • Weinberg, S.E., Sena, L.A., and Chandel, N.S. (2015). Mitochondria in the regulation of innate and adaptive immunity. Immunity 42, 406–417.

    PubMed  PubMed Central  CAS  Google Scholar 

  • Wu, G., and Meininger, C.J. (2002). Regulation of nitric oxide synthesis by dietary factors. Annu Rev Nutr 22, 61–86.

    PubMed  CAS  Google Scholar 

  • Wu, Y., Hu, Y., Wang, B., Li, S., Ma, C., Liu, X., Moynagh, P.N., Zhou, J., and Yang, S. (2020). Dopamine uses the DRD5-ARRB2-PP2A signaling axis to block the TRAF6-mediated NF-κB pathway and suppress systemic inflammation. Mol Cell 78, 42–56.e6.

    PubMed  CAS  Google Scholar 

  • Xia, Y., Chen, S., Zeng, S., Zhao, Y., Zhu, C., Deng, B., Zhu, G., Yin, Y., Wang, W., Hardeland, R., et al. (2019). Melatonin in macrophage biology: current understanding and future perspectives. J Pineal Res 66, e12547.

    PubMed  Google Scholar 

  • Xia, Y., He, F., Wu, X., Tan, B., Chen, S., Liao, Y., Qi, M., Chen, S., Peng, Y., Yin, Y., et al. (2021). GABA transporter sustains IL-1β production in macrophages. Sci Adv 7, eabe9274.

    PubMed  PubMed Central  CAS  Google Scholar 

  • Xia, Y., Zhang, Q., Ye, Y., Wu, X., He, F., Peng, Y., Yin, Y., and Ren, W. (2022). Melatonergic signalling instructs transcriptional inhibition of IFNGR2 to lessen interleukin-1α-dependent inflammation. Clin Transl Med 12.

  • Xie, J.H., Li, Y.Y., and Jin, J. (2020). The essential functions of mitochondrial dynamics in immune cells. Cell Mol Immunol 17, 712–721.

    PubMed  PubMed Central  CAS  Google Scholar 

  • Yang, B., Wang, X., and Ren, X. (2012). Amino acid metabolism related to immune tolerance by MDSCs. Int Rev Immunol 31, 177–183.

    PubMed  Google Scholar 

  • Yin, M., and O’Neill, L.A.J. (2021). The role of the electron transport chain in immunity. FASEB J 35, e21974.

    PubMed  CAS  Google Scholar 

  • Zangerle, R., Kurz, K., Neurauter, G., Kitchen, M., Sarcletti, M., and Fuchs, D. (2010). Increased blood phenylalanine to tyrosine ratio in HIV-1 infection and correction following effective antiretroviral therapy. Brain Behav Immun 24, 403–408.

    PubMed  CAS  Google Scholar 

  • Zhang, Q., Zhao, K., Shen, Q., Han, Y., Gu, Y., Li, X., Zhao, D., Liu, Y., Wang, C., Zhang, X., et al. (2015). Tet2 is required to resolve inflammation by recruiting Hdac2 to specifically repress IL-6. Nature 525, 389–393.

    PubMed  PubMed Central  CAS  Google Scholar 

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (32225047, 31922079) and the Laboratory of Lingnan Modern Agriculture Project (NT2021005).

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  1. Contributed equally to this work

Authors and Affiliations

  1. Guangdong Laboratory of Lingnan Modern Agriculture, National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, 510642, China

    Qingzhuo Zhang, Siyuan Chen, Yan Guo, Jian Fu & Wenkai Ren

  2. College of Animal Science and Technology, Southwest University, Chongqing, 400715, China

    Fang He

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  1. Qingzhuo Zhang
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  2. Siyuan Chen
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  3. Yan Guo
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  4. Fang He
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Correspondence to Wenkai Ren.

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Compliance and ethics The author(s) declare that they have no conflict of interest. The animal study was reviewed and approved by the Laboratory Animal Ethical Commission of the South China Agricultural University.

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Zhang, Q., Chen, S., Guo, Y. et al. Phenylalanine diminishes M1 macrophage inflammation. Sci. China Life Sci. 66, 2862–2876 (2023). https://doi.org/10.1007/s11427-022-2296-0

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