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Obesity shifts house dust mite-induced airway cellular infiltration from eosinophils to macrophages: effects of glucocorticoid treatment

Abstract

Although classically characterized by chronic airway inflammation with eosinophil infiltration, asthma is a complex and multifactorial condition with numerous clinical phenotypes. Epidemiological studies strongly support the link between obesity and asthma and suggest that obesity precedes and promotes asthma development, increases asthma severity, and reduces steroid responsivity. Using a house dust mite (HDM) model of airway hyperresponsiveness in C57BL/6 mice, we examined the effects of diet-induced obesity on allergic airway inflammation and its treatment with dexamethasone. When compared to lean mice treated with HDM, obese-HDM mice had reduced plasma adiponectin, an anti-inflammatory adipokine, lower eosinophil and higher macrophage infiltration into the lungs and bronchoalveolar lavage (BAL) fluid, increased expression of total, M1, and M2 macrophage markers in the lungs, and enhanced Th2 and non-Th2 cytokine expression in the lungs. While Th2-associated responses in obese-HDM mice were suppressed by systemic dexamethasone, several Th2-independent responses, including total and M1 macrophage markers in the lungs, and lung CXC-motif ligand 1 (CXCL1) levels, were not improved following dexamethasone treatment. Thus, HDM combined with obesity promotes mixed localized inflammatory responses (e.g., M1, M2, Th1, and Th2) and shifts the cellular infiltration from eosinophils to macrophages, which are less sensitive to dexamethasone regulation. Because obese asthmatics exhibit more severe symptoms, lack a predominance of Th2 biomarkers, and are predicted to experience more steroid resistance when compared to lean asthmatics, this model could be used to study blunted steroid responses in obese-HDM mice and to define the macrophages found in the lungs.

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Abbreviations

ANOVA:

Analysis of variance

BAL:

Bronchoalveolar lavage

CXCL1:

CXC-motif ligand 1

Dex:

Dexamethasone

GRα:

Glucocorticoid receptor alpha

GRβ:

Glucocorticoid receptor beta

HDM:

House dust mite

H&E:

Hematoxylin and eosin

HFD:

High-fat diet

qPCR:

Quantitative polymerase chain reaction

References

  1. 1.

    Yang L, Colditz GA: Prevalence of overweight and obesity in the United States, 2007–2012. JAMA Intern Med. 2015;175(8):1412–3.

  2. 2.

    Grant RW, Stephens JM. Fat in flames: Influence of cytokines and pattern recognition receptors on adipocyte lipolysis. Am J Physiol Endocrinol Metab. 2015;309(3):E205–13.

  3. 3.

    Agrawal A, Mabalirajan U, Ahmad T, Ghosh B. Emerging interface between metabolic syndrome and asthma. Am J Respir Cell Mol Biol. 2011;44:270–5.

  4. 4.

    CDC Asthma Data and Surveillance. http://www.cdc.gov/asthma/asthmadata.htm. 2015.

  5. 5.

    Delgado J, Barranco P, Quirce S. Obesity and asthma. J Investig Allergol Clin Immunol. 2008;18:420–5.

  6. 6.

    Beuther DA. Recent insight into obesity and asthma. Curr Opin Pulm Med. 2010;16:64–70.

  7. 7.

    Beuther DA, Sutherland ER. Overweight, obesity, and incident asthma: a meta-analysis of prospective epidemiologic studies. Am J Respir Crit Care Med. 2007;175:661–6.

  8. 8.

    Thuesen BH, Husemoen LL, Hersoug LG, Pisinger C, Linneberg A. Insulin resistance as a predictor of incident asthma-like symptoms in adults. Clin Exp Allergy. 2009;39:700–7.

  9. 9.

    Hjellvik V, Tverdal A, Furu K. Body mass index as predictor for asthma: a cohort study of 118,723 males and females. Eur Respir J. 2010;35:1235–42.

  10. 10.

    Weiss ST. Obesity: insight into the origins of asthma. Nat Immunol. 2005;6:537–9.

  11. 11.

    Wenzel SE. Asthma phenotypes: the evolution from clinical to molecular approaches. Nat Med. 2012;18:716–25.

  12. 12.

    Boulet LP, Franssen E. Influence of obesity on response to fluticasone with or without salmeterol in moderate asthma. Respir Med. 2007;101:2240–7.

  13. 13.

    Peters-Golden M, Swern A, Bird SS, Hustad CM, Grant E, Edelman JM. Influence of body mass index on the response to asthma controller agents. Eur Respir J. 2006;27:495–503.

  14. 14.

    Johnson JR, Wiley RE, Fattouh R, Swirski FK, Gajewska BU, Coyle AJ, Gutierrez-Ramos JC, Ellis R, Inman MD, Jordana M. Continuous exposure to house dust mite elicits chronic airway inflammation and structural remodeling. Am J Respir Crit Care Med. 2004;169:378–85.

  15. 15.

    Yao X, Dai C, Fredriksson K, Lam J, Gao M, Keeran KJ, Nugent GZ, Qu X, Yu ZX, Jeffries N, Lin J, Kaler M, Shamburek R, Costello R, Csako G, Dahl M, Nordestgaard BG, Remaley AT, Levine SJ. Human apolipoprotein E genotypes differentially modify house dust mite-induced airway disease in mice. Am J Physiol Lung Cell Mol Physiol. 2012;302:L206–15.

  16. 16.

    Papapetropoulos A, Simoes DC, Xanthou G, Roussos C, Gratziou C. Soluble guanylyl cyclase expression is reduced in allergic asthma. Am J Physiol Lung Cell Mol Physiol. 2006;290:L179–84.

  17. 17.

    Meyerholz DK, Griffin MA, Castilow EM, Varga SM. Comparison of histochemical methods for murine eosinophil detection in an RSV vaccine-enhanced inflammation model. Toxicol Pathol. 2009;37:249–55.

  18. 18.

    Solanki MH, Chatterjee PK, Gupta M, Xue X, Plagov A, Metz MH, Mintz R, Singhal PC, Metz CN. Magnesium protects against cisplatin-induced acute kidney injury by regulating platinum accumulation. Am J Physiol Renal Physiol. 2014;307:F369–84.

  19. 19.

    Hinds TD Jr, Ramakrishnan S, Cash HA, Stechschulte LA, Heinrich G, Najjar SM, Sanchez ER. Discovery of glucocorticoid receptor-beta in mice with a role in metabolism. Mol Endocrinol. 2010;24:1715–27.

  20. 20.

    Nigro E, Daniele A, Scudiero O, Ludovica MM, Roviezzo F, D’Agostino B, Mazzarella G, Bianco A. Adiponectin in asthma: implications for phenotyping. Curr Protein Pept Sci. 2015;16:182–7.

  21. 21.

    Hossain MM, Mukheem A, Kamarul T. The prevention and treatment of hypoadiponectinemia-associated human diseases by up-regulation of plasma adiponectin. Life Sci. 2015;135:55–67. doi:10.1016/j.lfs.2015.03.010.

  22. 22.

    Kips JC, Tournoy KG, Pauwels RA. New anti-asthma therapies: suppression of the effect of interleukin (IL)-4 and IL-5. Eur Respir J. 2001;17:499–506.

  23. 23.

    Ahmed M, Gaffen SL. IL-17 in obesity and adipogenesis. Cytokine Growth Factor Rev. 2010;21:449–53.

  24. 24.

    Wang YH, Wills-Karp M. The potential role of interleukin-17 in severe asthma. Curr Allergy Asthma Rep. 2011;11:388–94.

  25. 25.

    McKinley L, Alcorn JF, Peterson A, Dupont RB, Kapadia S, Logar A, Henry A, Irvin CG, Piganelli JD, Ray A, Kolls JK. TH17 cells mediate steroid-resistant airway inflammation and airway hyperresponsiveness in mice. J Immunol. 2008;181:4089–97.

  26. 26.

    Fujie H, Niu K, Ohba M, Tomioka Y, Kitazawa H, Nagashima K, Ohrui T, Numasaki M. A distinct regulatory role of Th17 cytokines IL-17A and IL-17F in chemokine secretion from lung microvascular endothelial cells. Inflammation. 2012;35:1119–31.

  27. 27.

    Park H, Li Z, Yang XO, Chang SH, Nurieva R, Wang YH, Wang Y, Hood L, Zhu Z, Tian Q, Dong C. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol. 2005;6:1133–41.

  28. 28.

    Barnes PJ. Mechanisms and resistance in glucocorticoid control of inflammation. J Steroid Biochem Mol Biol. 2010;120:76–85.

  29. 29.

    Dennis RJ, Solarte I, Rodrigo G. Asthma in adults. BMJ Clin Evid. 2011; pii: 1512.

  30. 30.

    Gibeon D, Batuwita K, Osmond M, Heaney LG, Brightling CE, Niven R, Mansur A, Chaudhuri R, Bucknall CE, Rowe A, Guo Y, Bhavsar PK, Chung KF, Menzies-Gow A. Obesity-associated severe asthma represents a distinct clinical phenotype: analysis of the British Thoracic Society Difficult Asthma Registry Patient cohort according to BMI. Chest. 2013;143:406–14.

  31. 31.

    Lugogo NL, Kraft M, Dixon AE. Does obesity produce a distinct asthma phenotype? J Appl Physiol. 1985;2010(108):729–34.

  32. 32.

    Swinburn BA, Sacks G, Hall KD, McPherson K, Finegood DT, Moodie ML, Gortmaker SL. The global obesity pandemic: shaped by global drivers and local environments. Lancet. 2011;378:804–14.

  33. 33.

    Hedley AA, Ogden CL, Johnson CL, Carroll MD, Curtin LR, Flegal KM. Prevalence of overweight and obesity among US children, adolescents, and adults, 1999–2002. JAMA. 2004;291:2847–50.

  34. 34.

    Davidson JM, Covar RA, Brown E, Spahn JD. Does obesity influence steroid absorption, metabolism, and in vitro steroid response in adults with severe asthma. J. Allergy Clin. Immunol. 2009;123:156–9.

  35. 35.

    Medoff BD, Okamoto Y, Leyton P, Weng M, Sandall BP, Raher MJ, Kihara S, Bloch KD, Libby P, Luster AD. Adiponectin deficiency increases allergic airway inflammation and pulmonary vascular remodeling. Am J Respir Cell Mol Biol. 2009;41:397–406.

  36. 36.

    Williams AS, Kasahara DI, Verbout NG, Fedulov AV, Zhu M, Si H, Wurmbrand AP, Hug C, Ranscht B, Shore SA. Role of the adiponectin binding protein, T-cadherin (Cdh13), in allergic airways responses in mice. PLoS ONE. 2012;7:e41088.

  37. 37.

    Lovren F, Pan Y, Quan A, Szmitko PE, Singh KK, Shukla PC, Gupta M, Chan L, Al-Omran M, Teoh H, Verma S. Adiponectin primes human monocytes into alternative anti-inflammatory M2 macrophages. Am J Physiol Heart Circ Physiol. 2010;299:H656–63.

  38. 38.

    Shore SA, Terry RD, Flynt L, Xu A, Hug C. Adiponectin attenuates allergen-induced airway inflammation and hyperresponsiveness in mice. J Allergy Clin Immunol. 2006;118:389–95.

  39. 39.

    Gawa-Yamauchi M, Moss KA, Bovenkerk JE, Shankar SS, Morrison CL, Lelliott CJ, Vidal-Puig A, Jones R, Considine RV. Regulation of adiponectin expression in human adipocytes: effects of adiposity, glucocorticoids, and tumor necrosis factor alpha. Obes Res. 2005;13:662–9.

  40. 40.

    Halleux CM, Takahashi M, Delporte ML, Detry R, Funahashi T, Matsuzawa Y, Brichard SM. Secretion of adiponectin and regulation of apM1 gene expression in human visceral adipose tissue. Biochem Biophys Res Commun. 2001;288:1102–7.

  41. 41.

    Johnson JR, Wiley RE, Fattouh R, Swirski FK, Gajewska BU, Coyle AJ, Gutierrez-Ramos JC, Ellis R, Inman MD, Jordana M. Continuous exposure to house dust mite elicits chronic airway inflammation and structural remodeling. Am J Respir Crit Care Med. 2004;169:378–85.

  42. 42.

    Gueders MM, Paulissen G, Crahay C, Quesada-Calvo F, Hacha J, Van HC, Tournoy K, Louis R, Foidart JM, Noel A, Cataldo DD. Mouse models of asthma: a comparison between C57BL/6 and BALB/c strains regarding bronchial responsiveness, inflammation, and cytokine production. Inflamm Res. 2009;58:845–54.

  43. 43.

    Yang M, Kumar RK, Hansbro PM, Foster PS. Emerging roles of pulmonary macrophages in driving the development of severe asthma. J Leukoc Biol. 2012;91:557–69.

  44. 44.

    Bhavsar P, Hew M, Khorasani N, Torrego A, Barnes PJ, Adcock I, Chung KF. Relative corticosteroid insensitivity of alveolar macrophages in severe asthma compared with non-severe asthma. Thorax. 2008;63:784–90.

  45. 45.

    Haldar P, Pavord ID, Shaw DE, Berry MA, Thomas M, Brightling CE, Wardlaw AJ, Green RH. Cluster analysis and clinical asthma phenotypes. Am J Respir Crit Care Med. 2008;178:218–24.

  46. 46.

    Leiria LO, Martins MA, Saad MJ. Obesity and asthma: beyond T(H)2 inflammation. Metabolism. 2015;64:172–81.

  47. 47.

    Traves SL, Donnelly LE. Th17 cells in airway diseases. Curr Mol Med. 2008;8:416–26.

  48. 48.

    Hong JY, Chung Y, Steenrod J, Chen Q, Lei J, Comstock AT, Goldsmith AM, Bentley JK, Sajjan US, Hershenson MB. Macrophage activation state determines the response to rhinovirus infection in a mouse model of allergic asthma. Respir Res. 2014;15:63. doi:10.1186/1465-9921-15-63.:63-15.

  49. 49.

    Shore SA. Obesity and asthma: possible mechanisms. J Allergy Clin Immunol. 2008;121:1087–93.

  50. 50.

    Hong JY, Chung Y, Steenrod J, Chen Q, Lei J, Comstock AT, Goldsmith AM, Bentley JK, Sajjan US, Hershenson MB. Macrophage activation state determines the response to rhinovirus infection in a mouse model of allergic asthma. Respir Res. 2014;15:63. doi:10.1186/1465-9921-15-63.:63-15.

  51. 51.

    Melgert BN, Oriss TB, Xon-McCarthy B, Geerlings M, Hylkema MN, Ray A, Qi Z. Macrophages: regulators of sex differences in asthma? Am J Respir Cell Mol Biol. 2010;42:595–603.

  52. 52.

    Melgert BN, ten Hacken NH, Rutgers B, Timens W, Postma DS, Hylkema MN. More alternative activation of macrophages in lungs of asthmatic patients. J Allergy Clin Immunol. 2011;127:831–3.

  53. 53.

    Draijer C, Robbe P, Boorsma CE, Hylkema MN, Melgert BN. Characterization of macrophage phenotypes in three murine models of house-dust-mite-induced asthma. Mediators Inflamm. 2013; 632049. doi:10.1155/2013/632049.

  54. 54.

    Nieuwenhuizen NE, Kirstein F, Jayakumar J, Emedi B, Hurdayal R, Horsnell WG, Lopata AL, Brombacher F. Allergic airway disease is unaffected by the absence of IL-4Ralpha-dependent alternatively activated macrophages. J Allergy Clin Immunol. 2012;130:743–50.

  55. 55.

    Goleva E, Hauk PJ, Hall CF, Liu AH, Riches DW, Martin RJ, Leung DY. Corticosteroid-resistant asthma is associated with classical antimicrobial activation of airway macrophages. J Allergy Clin Immunol. 2008;122:550–9.

  56. 56.

    Cancello R, Henegar C, Viguerie N, Taleb S, Poitou C, Rouault C, Coupaye M, Pelloux V, Hugol D, Bouillot JL, Bouloumie A, Barbatelli G, Cinti S, Svensson PA, Barsh GS, Zucker JD, Basdevant A, Langin D, Clement K. Reduction of macrophage infiltration and chemoattractant gene expression changes in white adipose tissue of morbidly obese subjects after surgery-induced weight loss. Diabetes. 2005;54:2277–86.

  57. 57.

    Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest. 2003;112:1796–808.

  58. 58.

    Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, Sole J, Nichols A, Ross JS, Tartaglia LA, Chen H. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest. 2003;112:1821–30.

  59. 59.

    Martinez FO, Gordon S. The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000Prime Rep. 2014;6:13. doi:10.12703/P6-13.

  60. 60.

    Lumeng CN, Bodzin JL, Saltiel AR. Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest. 2007;117:175–84.

  61. 61.

    Gordon S. Alternative activation of macrophages. Nat Rev Immunol. 2003;3:23–35.

  62. 62.

    Raes G, Brys L, Dahal BK, Brandt J, Grooten J, Brombacher F, Vanham G, Noel W, Bogaert P, Boonefaes T, Kindt A, Van den BR, Leenen PJ, De BP, Ghassabeh GH. Macrophage galactose-type C-type lectins as novel markers for alternatively activated macrophages elicited by parasitic infections and allergic airway inflammation. J Leukoc Biol. 2005;77:321–7.

  63. 63.

    Ulrich K, Hincks JS, Walsh R, Wetterstrand EM, Fidock MD, Sreckovic S, Lamb DJ, Douglas GJ, Yeadon M, Perros-Huguet C, Evans SM. Anti-inflammatory modulation of chronic airway inflammation in the murine house dust mite model. Pulm Pharmacol Ther. 2008;21:637–47.

  64. 64.

    Rhen T, Cidlowski JA. Antiinflammatory action of glucocorticoids–new mechanisms for old drugs. N Engl J Med. 2005;353:1711–23.

  65. 65.

    Hamid QA, Wenzel SE, Hauk PJ, Tsicopoulos A, Wallaert B, Lafitte JJ, Chrousos GP, Szefler SJ, Leung DY. Increased glucocorticoid receptor beta in airway cells of glucocorticoid-insensitive asthma. Am J Respir Crit Care Med. 1999;159:1600–4.

  66. 66.

    Goleva E, Li LB, Eves PT, Strand MJ, Martin RJ, Leung DY. Increased glucocorticoid receptor beta alters steroid response in glucocorticoid-insensitive asthma. Am J Respir Crit Care Med. 2006;173:607–16.

  67. 67.

    Christodoulopoulos P, Leung DY, Elliott MW, Hogg JC, Muro S, Toda M, Laberge S, Hamid QA. Increased number of glucocorticoid receptor-beta-expressing cells in the airways in fatal asthma. J Allergy Clin Immunol. 2000;106:479–84.

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Acknowledgments

JD and LH were Fellows supported by a T32 training grant (AI083223-06, V Bonagura PI), the Feinstein Institute for Medical Research, and Hofstra North Shore-LIJ School of Medicine (LW).

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Correspondence to C. N. Metz.

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Diaz, J., Warren, L., Helfner, L. et al. Obesity shifts house dust mite-induced airway cellular infiltration from eosinophils to macrophages: effects of glucocorticoid treatment. Immunol Res 63, 197–208 (2015) doi:10.1007/s12026-015-8717-2

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Keywords

  • Asthma
  • Steroid resistance
  • Airway inflammation
  • Diet-induced obesity