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Bee venom phospholipase A2 ameliorates amyotrophic lateral sclerosis by increasing regulatory T cell population

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Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that primarily affects the nerve cells responsible for controlling voluntary muscle movement in the brain and spinal cord, causing loss of muscle control. Moreover, other researchers have reported that BV phospholipase A2 (bvPLA2) has neuroprotective effects in a mouse model of Alzheimer’s disease (AD). The aim of this study was to investigate whether bvPLA2 alleviates the pathological features of ALS by affecting Tregs in SOD1 mice. SOD1-G93A mice were used as the ALS model. The mice (75-days old) were administered phosphate buffered saline (PBS) or bvPLA2 (0.5 mg/kg) twice a week. The results demonstrated that the body and hindlimb weights of PBS-treated SOD1 mice were lower than those of wild-type mice, whereas that of bvPLA2-treated SOD1 mice increased compared to that of PBS-treated SOD1 mice. Motor function also decreased to a lesser extent in bvPLA2-treated SOD1 mice, whereas that of PBS-treated SOD1 mice was significantly impaired compared to wild-type mice. Moreover, bvPLA2-treated SOD1 mice had greater number of intact motor neurons in their lumbar spinal cord compared to PBS-treated SOD1 mice. The level of Tregs in the TA muscle was also higher in bvPLA2-treated SOD1 mice than in PBS-treated SOD1 mice. Lastly, bvPLA2-treated SOD1 mice showed less increase in levels of NOS2 and TNF-α and lower levels of IL-4 and IL-10 compared to PBS-treated SOD1 mice. Thus, our data suggest that bvPLA2 alleviates the progress of ALS by inducing a Treg-mediated anti-inflammatory response.

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References

  • Akimova T, Beier UH, Wang L, Levine MH and Hancock WW (2011) Helios expression is a marker of T cell activation and proliferation. PLoS One 6(8):e24226

  • Alves CJ, de Santana LP et al (2011) Early motor and electrophysiological changes in transgenic mouse model of amyotrophic lateral sclerosis and gender differences on clinical outcome. Brain Res 1394:90–104

    Article  CAS  Google Scholar 

  • Annacker O, Asseman C, Read S, Powrie F (2003) Interleukin-10 in the regulation of T cell-induced colitis. J Autoimmun 20(4):277–279

    Article  CAS  Google Scholar 

  • Baek H, Jang HI, Jeon HN, Bae H (2018) Comparison of administration routes on the protective effects of bee venom phospholipase A2 in a mouse model of Parkinson’s disease. Front Aging Neurosci 10:179

    Article  Google Scholar 

  • Bettelli E, Carrier Y et al (2006) Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441(7090):235–238

    Article  CAS  Google Scholar 

  • Brown RH Jr, Al-Chalabi A (2017) Amyotrophic lateral sclerosis. N Engl J Med 377(16):1602

    Article  Google Scholar 

  • Burrell JR, Kiernan MC, Vucic S, Hodges JR (2011) Motor neuron dysfunction in frontotemporal dementia. Brain 134(Pt 9):2582–2594

    Article  Google Scholar 

  • Cereda C, Baiocchi C et al (2008) TNF and sTNFR1/2 plasma levels in ALS patients. J Neuroimmunol 194(1–2):123–131

    Article  CAS  Google Scholar 

  • Chung ES, Lee G et al (2015) Bee Venom phospholipase a2, a novel foxp3+ regulatory t cell inducer, protects dopaminergic neurons by modulating neuroinflammatory responses in a mouse model of Parkinson’s disease. J Immunol 195(10):4853–4860

    Article  CAS  Google Scholar 

  • Curiel TJ (2007) Tregs and rethinking cancer immunotherapy. J Clin Invest 117(5):1167–1174

    Article  CAS  Google Scholar 

  • Giovannelli I, Heath P, Shaw PJ, Kirby J (2020) The involvement of regulatory T cells in amyotrophic lateral sclerosis and their therapeutic potential. Amyotroph Lateral Scler Frontotemporal Degener 21(5–6):435–444

    Article  CAS  Google Scholar 

  • Gliwinski M, Iwaszkiewicz-Grzes D, Trzonkowski P (2017) Cell-based therapies with T regulatory cells. BioDrugs 31(4):335–347

    Article  CAS  Google Scholar 

  • Gomes MDM (2019) Franz Nissl (1860–1919), noted neuropsychiatrist and neuropathologist, staining the neuron, but not limiting it. Dement Neuropsychol 13(3):352–355

    Article  Google Scholar 

  • Hardiman O, Al-Chalabi A et al (2017) Amyotrophic lateral sclerosis. Nat Rev Dis Primers 3:17085

    Article  Google Scholar 

  • Hensley K, Fedynyshyn J et al (2003) Message and protein-level elevation of tumor necrosis factor alpha (TNF alpha) and TNF alpha-modulating cytokines in spinal cords of the G93A-SOD1 mouse model for amyotrophic lateral sclerosis. Neurobiol Dis 14(1):74–80

    Article  CAS  Google Scholar 

  • Hooten KG, Beers DR, Zhao W, Appel SH (2015) Protective and Toxic Neuroinflammation in Amyotrophic Lateral Sclerosis. Neurotherapeutics 12(2):364–375

    Article  CAS  Google Scholar 

  • Hori S, Nomura T, Sakaguchi S (2003) Control of regulatory T cell development by the transcription factor Foxp3. Science 299(5609):1057–1061

    Article  CAS  Google Scholar 

  • Jung KH, Baek H et al. (2016) Protective Effects of Intratracheally-Administered Bee Venom Phospholipase A2 on Ovalbumin-Induced Allergic Asthma in Mice. Toxins (Basel) 8(10):1

  • Kim H, Lee H et al (2015) Phospholipase A2 inhibits cisplatin-induced acute kidney injury by modulating regulatory T cells by the CD206 mannose receptor. Kidney Int 88(3):550–559

    Article  CAS  Google Scholar 

  • Kwon YB, Lee JD et al (2001) Bee venom injection into an acupuncture point reduces arthritis associated edema and nociceptive responses. Pain 90(3):271–280

    Article  Google Scholar 

  • Lasiene J and Yamanaka K (2011) Glial cells in amyotrophic lateral sclerosis. Neurol Res Int 2011:718987

  • Lee SM, Lim J, Lee JD, Choi DY, Lee S (2014) Bee venom treatment for refractory postherpetic neuralgia: a case report. J Altern Complement Med 20(3):212–214

    Article  Google Scholar 

  • Li D, Lee Y, Kim W, Lee K, Bae H, Kim SK (2015) Analgesic Effects of Bee Venom Derived Phospholipase A(2) in a Mouse Model of Oxaliplatin-Induced Neuropathic Pain. Toxins (basel) 7(7):2422–2434

    Article  Google Scholar 

  • Linderoth L, Peters GH, Jorgensen K, Madsen R, Andresen TL (2007) Synthesis of sn-1 functionalized phospholipids as substrates for secretory phospholipase A2. Chem Phys Lipids 146(1):54–66

    Article  CAS  Google Scholar 

  • Liu XD, Zhang JL, Zheng HG, Liu FY, Chen Y (2008) Clinical randomized study of bee-sting therapy for rheumatoid arthritis. Zhen Ci Yan Jiu 33(3):197–200

    PubMed  Google Scholar 

  • Mantovani S, Garbelli S et al (2009) Immune system alterations in sporadic amyotrophic lateral sclerosis patients suggest an ongoing neuroinflammatory process. J Neuroimmunol 210(1–2):73–79

    Article  CAS  Google Scholar 

  • Masrori P, Van Damme P (2020) Amyotrophic lateral sclerosis: a clinical review. Eur J Neurol 27(10):1918–1929

    Article  CAS  Google Scholar 

  • McCauley ME, Baloh RH (2019) Inflammation in ALS/FTD pathogenesis. Acta Neuropathol 137(5):715–730

    Article  CAS  Google Scholar 

  • McCombe PA, Henderson RD (2011) The Role of immune and inflammatory mechanisms in ALS. Curr Mol Med 11(3):246–254

    Article  CAS  Google Scholar 

  • McGoldrick P, Joyce PI, Fisher EM and Greensmith L (2013) Rodent models of amyotrophic lateral sclerosis. Biochim Biophys Acta 1832(9):1421-1436

  • Mousavi SM, Imani S, Haghighi S, Mousavi SE, Karimi A (2012) Effect of Iranian Honey bee (Apis mellifera) Venom on Blood Glucose and Insulin in Diabetic Rats. J Arthropod Borne Dis 6(2):136–143

    PubMed  PubMed Central  Google Scholar 

  • Murdock BJ, Zhou T, Kashlan SR, Little RJ, Goutman SA, Feldman EL (2017) Correlation of Peripheral Immunity With Rapid Amyotrophic Lateral Sclerosis Progression. JAMA Neurol 74(12):1446–1454

    Article  Google Scholar 

  • Neary D, Snowden JS et al (1998) Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology 51(6):1546–1554

    Article  CAS  Google Scholar 

  • Park S, Baek H et al (2015) Bee venom phospholipase A2 suppresses allergic airway inflammation in an ovalbumin-induced asthma model through the induction of regulatory T cells. Immun Inflamm Dis 3(4):386–397

    Article  CAS  Google Scholar 

  • Phukan J, Pender NP, Hardiman O (2007) Cognitive impairment in amyotrophic lateral sclerosis. Lancet Neurol 6(11):994–1003

    Article  CAS  Google Scholar 

  • Poloni M, Facchetti D et al (2000) Circulating levels of tumour necrosis factor-alpha and its soluble receptors are increased in the blood of patients with amyotrophic lateral sclerosis. Neurosci Lett 287(3):211–214

    Article  CAS  Google Scholar 

  • Read S, Malmstrom V, Powrie F (2000) Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25(+)CD4(+) regulatory cells that control intestinal inflammation. J Exp Med 192(2):295–302

    Article  CAS  Google Scholar 

  • Rosen DR (1993) Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 364(6435):362

    Article  CAS  Google Scholar 

  • Senel E, Kuyucu M, Suslu I (2014) Honey and bee venom in dermatology: A novel possible alternative or complimentary therapy for psoriasis vulgaris. Anc Sci Life 33(3):192–193

    Article  Google Scholar 

  • Sheean RK, McKay FC et al (2018) Association of Regulatory T-Cell Expansion With Progression of Amyotrophic Lateral Sclerosis: A Study of Humans and a Transgenic Mouse Model. JAMA Neurol 75(6):681–689

    Article  Google Scholar 

  • van Es MA, Hardiman O et al (2017) Amyotrophic lateral sclerosis. Lancet 390(10107):2084–2098

    Article  Google Scholar 

  • Ye M, Chung HS et al (2016) Neuroprotective effects of bee venom phospholipase A2 in the 3xTg AD mouse model of Alzheimer’s disease. J Neuroinflammation 13:10

    Article  Google Scholar 

  • Zhao W, Beers DR, Liao B, Henkel JS, Appel SH (2012) Regulatory T lymphocytes from ALS mice suppress microglia and effector T lymphocytes through different cytokine-mediated mechanisms. Neurobiol Dis 48(3):418–428

    Article  CAS  Google Scholar 

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Acknowledgements

We would like to thank Elsevier (https://.webshop.elsevier.com) for English language editing.

Funding

This study was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT; NRF-2020R1A2B5B03002164).

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Authors and Affiliations

  1. Department of Physiology, College of Korean Medicine, Kyung Hee University, 26-6 Kyungheedae-ro, Dongdaemun-gu, Seoul, 02453, Republic of Korea

    Minwoo Hong, Ik-Hwan Han & Hyunsu Bae

  2. Department of Korean Medicine, College of Korean Medicine, Graduate School, Kyung Hee University, 26-6 Kyungheedae-ro, Dongdaemun-gu, Seoul, 02453, Republic of Korea

    Mi Jung Kang & Sehyun Pak

Authors
  1. Minwoo Hong
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  2. Mi Jung Kang
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  4. Ik-Hwan Han
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  5. Hyunsu Bae
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Contributions

Conceptualization: H.B.; Methodology: M.H., M.K.S.P. and I.-H.H.; Formal analysis and investigation: M.H. and M.K. Writing – review and editing: I.-H.H.; Fungding acquisition: H.B.; Resources: H.B.; Supervision: H.B. Approval of the manuscript: All authors.

Corresponding authors

Correspondence to Ik-Hwan Han or Hyunsu Bae.

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Ethical statement

All animal studies were approved by the University of Kyung Hee Institutional Animal Care and Use of Committee (KHUASP [SE]-20-529).

Conflict of interest

Minwoo Hong has no conflict of interest. Mi Jung Kang has no conflict of interest. Sehyun Pak has no conflict of interest. Ik‑Hwan Han has no conflict of interest. Hyunsu Bae has no conflict of interest.

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Hong, M., Kang, M.J., Pak, S. et al. Bee venom phospholipase A2 ameliorates amyotrophic lateral sclerosis by increasing regulatory T cell population. ADV TRADIT MED (ADTM) 22, 599–606 (2022). https://doi.org/10.1007/s13596-022-00631-9

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