Original Article
 

Ovariectomy Modifies TH2, and TH17 Balance in BALB/C Allergic Mice

Abstract

Asthma is a chronic inflammation of the airways affecting over 300 million people worldwide. As in the autoimmune diseases, it is well described that women are the most affected by asthma. The higher number of women presenting this pathology suggests the involvement of female sex hormones in the construction of the allergic immune response. Female Balb / c mice were used for the experiments. Thirty-eight animals were separated into four groups: OVX-Ova; Sham-Ova; OVX-Sal; Sham-Sal. Then animals underwent acute allergic induction protocol by Ovalbulmin (OVA). Ovariectomized animals showed greater number of leukocytes in bronchoalveolar lavage (BAL) and elevated white blood cells recruitment to the lung environment observed by histological analysis. There was a significant increase of eosinophils and mast cells in inflammatory sites at pulmonary tissue. The relative uterine and body weight were lower in ovariectomized animals and higher in Sham mice, respectively. Moreover, the lack of the sex hormones induced an increase in interleukin (IL)-4 and titers of immunoglobulin G1 (IgG1) antibodies. However, increased production of IL-17A was only observed in Sham animals. Altogether, data this study suggest that ovariectomy induces the formation of a stronger Th2 response in allergic animal. However, the immune processes involved in the allergic response in females currently remain unclear.

  1. Yao XJ, Huang KW, Li Y, Zhang Q, Wang JJ, Wang W, et al. Direct comparison of the dynamics of IL-25- and 'allergen'-induced airways inflammation, remodelling and hypersensitivity in a murine asthma model. Clin Exp Allergy 2014; 44(5):765-77.
  2. Asher I, Pearce N. Global burden of asthma among children. Int J Tuberc Lung Dis 2014; 18(11):1269-78.
  3. Masoli M, Fabian D, Holt S, Beasley R. The global burden of asthma: executive summary of the GINA Dissemination Committee report. Allergy 2004; 59(5):469-78.
  4. Wells AD, Poole JA, Romberger DJ. Influence of farming exposure on the development of asthma and asthma-like symptoms. Int. Immunopharmacol 2014; 23(1):356–63.
  5. Fu L, Freishtat RJ, Gordish-Dressman H, Teach SJ, Resca L, Hoffman EP, Wang Z. Natural progression of childhood asthma symptoms and Strong influence of sex and puberty. Ann Am Thorac Soc 2014; 11:939-44.
  6. Valkonen M, Wouters IM, Taubel M, Rintala H, Lenters V, Vasara R, et al. Bacterial Exposures and Associations with Atopy and Asthma in Children. PLoS One 2015; 10(6):e0131594.
  7. Tam A, Morrish D, Wadsworth S, Dorscheid D, Man SF, Sin DD. The role of female hormones on lung function in chronic lung diseases. BMC Womens Health 2011;11:24.
  8. Shah S. Hormonal link to autoimmune allergies. ISRN Allergy 2012; 2012:910437.
  9. Gibbs CJ, Coutts II, Lock R, Finnegan OC, White RJ. Premenstrual exacerbation of asthma. Thorax 1984; 39(11):833-6.
  10. Ensom MH, Chong G, Beaudin B, Bai TR. Estradiol in severe asthma with premenstrual worsening. Ann Pharmacother 2003; 37(11):1610-3.
  11. Lambrecht BN, Hammad H. The immunology of asthma. Nat Immunol 2015; 16(1):45-56.
  12. Ko FW, Lun SW, Wong CK, Szeto CC, Lam CW, Leung TF, et al. Decreased T-bet expression and changes in chemokine levels in adults with asthma. Clin Exp Immunol 2007; 147(3):526-32.
  13. Andersson CK, Bergqvist A, Mori M, Mauad T, Bjermer L, Erjefalt JS. Mast cell-associated alveolar inflammation in patients with atopic uncontrolled asthma. J Allergy Clin Immunol 2011; 127(4):905-12.
  14. Newcomb DC, Peebles RSJR. Th17-mediated inflammation in asthma. Curr Opin Immunol 2013; 25(6):755-60.
  15. Holgate ST, Polosa R. The mechanisms, diagnosis, and management of severe asthma in adults. Lancet 2006; 368(9537):780-93.
  16. Ivanov II, Zhou L, Littman DR. Transcriptional regulation of Th17 cell differentiation. Semin Immunol 2007; 19(6):409-17.
  17. Hartl D, Koller B, Mehlhorn AT, Reinhardt D, Nicolai T, Schendel DJ, et al. Quantitative and functional impairment of pulmonary CD4+CD25hi regulatory T cells in pediatric asthma. J Allergy Clin Immunol 2007; 119(5):1258-66.
  18. Zhao J, Lloyd CM, Noble A. Th17 responses in chronic allergic airway inflammation abrogate regulatory T-cell-mediated tolerance and contribute to airway remodeling. Mucosal Immunol 2013; 6(2):335-46.
  19. Zein JG, Erzurum SC. Asthma is Different in Women. Curr Allergy Asthma Rep 2015; 15(6):28.
  20. Ma LJ, Guzman EA, Deguzman A, Muller HK, Walker AM, Owen LB. Local cytokine levels associated with delayed-type hypersensitivity responses: modulation by gender, ovariectomy, and estrogen replacement. J Endocrinol 2007; 193(2):291-7.
  21. Robinson DS, Hamid Q, Jacobson M, Ying S, Kay AB, Durham SR. Evidence for Th2-type T helper cell control of allergic disease in vivo. Springer Semin Immunopathol 1993; 15(1):17-27.
  22. Robinson DS. Regulatory T cells and asthma. Clin Exp Allergy 2009; 39(9):1314-23.
  23. Antunes MA, Abreu SC, Silva AL, Parra-Cuentas ER, Ab'saber AM, Capelozzi VL, et al. Sex-specific lung remodeling and inflammation changes in experimental allergic asthma. J Appl Physiol 2010; 109(3):855-63.
  24. Draijer C, Hylkema MN, Boorsma CE, Klok PA, Robbe P, Timens W, et al. Sexual maturation protects against development of lung inflammation through estrogen. Am J Physiol Lung Cell Mol Physiol 2016; 310(2):L166-74.
  25. Oliveira AP, Peron JP, Santos F.A.L, Golega BA, Vieira RP, Ibanez OC, et al. Ovariectomized OVA-sensitized mice display increased frequency of CD4(+)Foxp3(+) T regulatory cells in the periphery. PLoS One 2013; 8:e65674.
  26. Card JW, Zeldin DC. Hormonal influences on lung function and response to environmental agents: lessons from animal models of respiratory disease. Proc Am Thorac Soc 2009; 6(7):588-95.
  27. Takeda M, Tanabe M, Ito W, Ueki S, Konnno Y, Chihara M, et al. Gender difference in allergic airway remodelling and immunoglobulin production in mouse model of asthma. Respirology 2013; 18(5):797-806.
  28. Viscardi RM, Kaplan J, Lovchik JC, He JR, Hester L, Rao S, et al. Characterization of a Murine Model of Ureaplasma urealyticum Pneumonia. Infect Immun 2002; 70(10):5721–29.
  29. Forno E, Gogna M, Cepeda A, Yanez A, Sole D, Cooper P, et al. Asthma in Latin America. Thorax 2015; 70(9):898-905.
  30. Townsend EA, Miller VM, Prakash YS. Sex differences and sex steroids in lung health and disease. Endocr Rev 2012; 33(1):1–47.
  31. Cai, Y, Zhou J, Webb DC. Estrogen stimulates Th2 cytokine production and regulates the compartmentalisation of eosinophils during allergen challenge in a mouse model of asthma. Int Arch Allergy Immunol 2012; 158(3):252-60.
  32. Kim DI, Choi MS, Pak SC, Lee SB, Jeon S. The effects of Sutaehwan-Gami on menopausal symptoms induced by ovariectomy in rats. BMC Complement Altern Med 2012; 12:227.
  33. Robinson DP, Hall OJ, Nilles TL, Bream JH, Klein SL. 17beta-estradiol protects females against influenza by recruiting neutrophils and increasing virus-specific CD8 T cell responses in the lungs. J Virol 2014; 88(9):4711-20.
  34. Chen YP, Zhang JH, Li CQ, Sun QX, Jiang XH. Obesity enhances Th2 inflammatory response via natural killer T cells in a murine model of allergic asthma. Int J Clin Exp Med 2015; 8(9):15403-12.
  35. Nappi RE, Kokot-Kierepa M. Vaginal Health: Insights, Views & Attitudes (VIVA) - results from an international survey. Climacteric 2012; 15(1):36-44.
  36. Davis S.R, Castelo-Branco C, Chedraui P, Lumsden MA, Nappi R E, Shah D, et al. Understanding weight gain at menopause. Climacteric 2012; 15(5):419-29.
  37. Johnston RA, Zhu M, Rivera-Sanchez YM, Lu FL, Theman TA, Flynt L, et al. Allergic Airway Responses in Obese Mice. American Journal Of Respiratory And Critical Care Medicine 2007; 176(7):650-58.
  38. Dimitropoulou C, Drakopanagiotakis F, Chatterjee A, Snead C, Catravas JD. Estrogen replacement therapy prevents airway dysfunction in a murine model of allergen-induced asthma. Lung 2009; 187(2):116-27.
  39. Matsubara S, Swasey CH, Loader JE, Dakhama A, Joetham A, Ohnishi H, et al. Estrogen determines sex differences in airway responsiveness after allergen exposure. Am J Respir Cell Mol Biol 2008; 38(5):501-08.
  40. Oliveira AP, Peron JP, Damazo AS, Franco AL, Domingos HV, Oliani SM, et al. Female sex hormones mediate the allergic lung reaction by regulating the release of inflammatory mediators and the expression of lung E-selectin in rats. Respir Res 2010; 11:2010.
  41. Oliveira AP, Domingos HV, Cavriani G, Damazo AS, Dos Santos F.A.L, et al. Cellular recruitment and cytokine generation in a rat model of allergic lung inflammation are differentially modulated by progesterone and estradiol. Am J Physiol Cell Physiol 2007; 293(3):C1120-28.
  42. Carey MA, Card JW, Bradbury JA, Moorman MP, Haykal-Coates N, Gavett SH, et al. Spontaneous airway hyperresponsiveness in estrogen receptor-alpha-deficient mice. Am J Respir Crit Care Med 2007; 175(2):126-35.
  43. Shah SP, Gohil PV, Shah GB. Role of estrogen receptor- alpha in an experimental model of bronchial asthma. Iran Biomed J 2010; 14(1-2):41-8.
  44. Nie H, Yang Q, Zhang G, Wang A, He Q, Liu M, et al. Invariant NKT cells act as an adjuvant to enhance Th2 inflammatory response in an OVA-induced mouse model of asthma. PLoS One 2015; 10(4):e0119901.
  45. Riffo-Vasquez Y, Ligeiro De Oliveira AP, Page CP, Spina D, Tavares-De-Lima W. Role of sex hormones in allergic inflammation in mice. Clin Exp Allergy 2007; 37(3):459-70.
  46. Itoga M, Konno Y, Moritoki Y, Saito Y, Ito W, Tamaki M, et al. G-Protein-Coupled Estrogen Receptor Agonist Suppresses Airway Inflammation in a Mouse Model of Asthma through IL-10. PLoS One 2015; 10(8):e0136326.
  47. Wei Y, Liu B, Sun J, Lv Y, Luo Q, Liu F, et al. Regulation of Th17/Treg function contributes to the attenuation of chronic airway inflammation by icariin in ovalbumin-induced murine asthma model. Immunobiology 2015; 220(6):789-97.
  48. Newcomb DC, Cephus JY, Boswell MG, Fahrenholz JM, Langley E W, Feldman AS, et al. Estrogen and progesterone decrease let-7f microRNA expression and increase IL-23/IL-23 receptor signaling and IL-17A production in patients with severe asthma. J Allergy Clin Immunol 2015; 136(4):1025-34.
  49. Li H, Hsu HC, Wu Q, Yang P, Li J, Luo B, et al. IL-23 promotes TCR-mediated negative selection of thymocytes through the upregulation of IL-23 receptor and RORgammat. Nat Commun 2014; 5:4259.
  50. Choy DF, Hart KM, Borthwick LA, Shikotra A, Nagarkar DR, Siddiqui S, et al.Th2 and Th17 inflammatory pathways are reciprocally regulated in asthma. Sci Transl Med 2015; 7(301):301ra129.

Files
IssueVol 16, No 6 (2017) QRcode
SectionOriginal Article(s)
Keywords
Airway inflammation Asthma IL-17A Ovariectomy Sex hormones

Rights and permissions
Creative Commons License This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
How to Cite
1.
Souza M, Lima F, Muniz I, Pereira Ítalo, Sousa L, Galantini M, Santos D, Figueiredo T, Silva R. Ovariectomy Modifies TH2, and TH17 Balance in BALB/C Allergic Mice. Iran J Allergy Asthma Immunol. 2017;16(6):525-536.