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Aging leads to dysfunctional innate immune responses to TLR2 and TLR4 agonists

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Abstract

Background

Sepsis is more common in the elderly. TNF⍺ is recognized as an important mediator in sepsis and Toll-like receptors (TLRs) play an important role in initiating signaling cascades to produce TNF⍺. Little is known about how innate immunity is altered in healthy human aging that predisposes to sepsis.

Aims and methods

We tested the hypothesis that aging dysregulates the innate immune response to TLR 2 and 4 ligands. We performed whole blood assays on 554 healthy subjects aged 40–80 years. TNFα production was measured at baseline and after stimulation with the TLR2 agonists: peptidoglycan, lipoteichoic acid, Pam3CysK, Zymosan A and the TLR4 agonist lipopolysaccharide (LPS). In a subset of subjects (n = 250), we measured Toll-like receptor (TLR) 2, 4 and MyD88 expression using real-time PCR.

Results and discussion

We measured a 2.5% increase per year in basal secretion of TNFα with aging (n = 554 p = 0.02). Likewise, TNFα secretion was increased with aging after stimulation with peptidoglycan (1.3% increase/year; p = 0.0005) and zymosan A (1.1% increase/year p = 0.03). We also examined the difference between baseline and stimulated TNFα for each individual. We found that the increase was driven by the elevated baseline levels. In fact, there was a diminished stimulated response to LPS (1.9% decrease/year; p = 0.05), lipoteichoic acid (2.1% decrease/year p = 0.03), and Pam3CysK (2.6% decrease/year p = 0.0007). There were no differences in TLR or MyD88 mRNA expression with aging, however, there was an inverse relationship between TLR expression and stimulated TNFα production.

Conclusions

With aging, circulating leukocytes produce high levels of TNFα at baseline and have inadequate responses to TLR2 and TLR4 agonists. These defects likely contribute to the increased susceptibility to sepsis in older adults.

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References

  1. Kochanek KD et al (2016) Deaths: final data for 2014. Nat Vital Stat Rep 65:1–122

    Google Scholar 

  2. Martin GS, Mannino DM, Moss M (2006) The effect of age on the development and outcome of adult sepsis. Crit Care Med 34:15–21

    Article  PubMed  Google Scholar 

  3. Pisani MA (2009) Analytic reviews: considerations in caring for the critically ill older patient. J Intensive Care Med 24:83–95

    Article  PubMed  Google Scholar 

  4. Dombrovskiy VY et al (2007) Rapid increase in hospitalization and mortality rates for severe sepsis in the United States: a trend analysis from 1993 to 2003. Crit Care Med 35:1244–1250

    Article  PubMed  Google Scholar 

  5. Grivennikov SI et al (2005) Distinct and nonredundant in vivo functions of TNF produced by t cells and macrophages/neutrophils: protective and deleterious effects. Immunity 22:93–104

    CAS  PubMed  Google Scholar 

  6. Ceramil A, Beutler B (1988) The role of cachectin/TNF in endotoxic shock and cachexia. Immunol Today 9:28–31

    Article  Google Scholar 

  7. Leon LR, White AA, Kluger MJ (1998) Role of IL-6 and TNF in thermoregulation and survival during sepsis in mice. Am J Physiol 275:R269–R277

    CAS  PubMed  Google Scholar 

  8. Debets JM et al (1989) Plasma tumor necrosis factor and mortality in critically ill septic patients. Crit Care Med 17:489–494

    Article  CAS  PubMed  Google Scholar 

  9. Shurin GV et al (2007) Dynamic alteration of soluble serum biomarkers in healthy aging. Cytokine 39:123–129

    Article  CAS  PubMed  Google Scholar 

  10. de Gonzalo-Calvo D et al (2010) Differential inflammatory responses in aging and disease: TNF-α and IL-6 as possible biomarkers. Free Radic Biol Med 49:733–737

    Article  CAS  PubMed  Google Scholar 

  11. Bruunsgaard H et al (2003) Elevated levels of tumor necrosis factor alpha and mortality in centenarians. Am J Med 115:278–283

    Article  CAS  PubMed  Google Scholar 

  12. Panda A et al (2010) Age-associated decrease in TLR function in primary human dendritic cells predicts influenza vaccine response. J Immunol 184:2518–2527

    Article  CAS  PubMed  Google Scholar 

  13. Boehmer ED et al (2005) Aging negatively skews macrophage TLR2- and TLR4-mediated pro-inflammatory responses without affecting the IL-2-stimulated pathway. Mech Ageing Dev 126:1305–1313

    Article  CAS  PubMed  Google Scholar 

  14. Gan WQ et al (2004) Association between chronic obstructive pulmonary disease and systemic inflammation: a systematic review and a meta-analysis. Thorax 59:574–580

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Sharafkhaneh A et al (2010) Burden of COPD in a government health care system: a retrospective observational study using data from the US Veterans Affairs population. Int J Chronic Obstr Pulm Dis 5:125

    Google Scholar 

  16. Harting JR et al (2012) Chronic obstructive pulmonary disease patients have greater systemic responsiveness to ex vivo stimulation with swine dust extract and its components versus healthy volunteers. J Toxicol Environ Health A 75:1456–1470

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. De Groote D et al (1992) Direct stimulation of cytokines (IL-1β, TNF-α, IL-6, IL-2, IFN-γ and GM-CSF) in whole blood. I. Comparison with isolated PBMC stimulation. Cytokine 4:239–248

    Article  PubMed  Google Scholar 

  18. Wyatt TA et al (2017) Alcohol inhibits organic dust-induced ICAM-1 expression on bronchial epithelial cells. Safety (Basel) 3:5

    Article  PubMed Central  Google Scholar 

  19. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods 25:402–408

    Article  CAS  PubMed  Google Scholar 

  20. Koster A et al (2006) Association of inflammatory markers with socioeconomic status. J Gerontol A Biol Sci Med Sci 61:284–290

    Article  PubMed  Google Scholar 

  21. Benjamini Y, Hochberg Y (1995) Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Ser B (Methodol) 57:289–300

    Google Scholar 

  22. Franceschi C, Campisi J (2014) Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. J Gerontol A Biol Sci Med Sci 69:S4–S9

    Article  PubMed  Google Scholar 

  23. Frankel JH et al (2018) Age-related immune responses after burn and inhalation injury are associated with altered clinical outcomes. Exp Gerontol 105:78–86

    Article  CAS  PubMed  Google Scholar 

  24. Marik PE, Zaloga GP), I. Norasept Ii Study Investigators (2001) North American Sepsis Trial, the effect of aging on circulating levels of proinflammatory cytokines during septic shock. Norasept II Study Investigators. J Am Geriatr Soc 49:5–9

    Article  CAS  PubMed  Google Scholar 

  25. Dalli J et al (2017) Human sepsis eicosanoid and proresolving lipid mediator temporal profiles: correlations with survival and clinical outcomes. Crit Care Med 45:58–68

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Dunston CR, Griffiths HR (2010) The effect of ageing on macrophage Toll-like receptor-mediated responses in the fight against pathogens. Clin Exp Immunol 161:407–416

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Qian F, Montgomery RR (2012) Quantitative imaging of lineage-specific Toll-like receptor-mediated signaling in monocytes and dendritic cells from small samples of human blood. J Vis Exp 62:e3741–e3741

    Google Scholar 

  28. Prasad AS (2014) Zinc: an antioxidant and anti-inflammatory agent: role of zinc in degenerative disorders of aging. J Trace Elem Med Biol 28:364–371

    Article  CAS  PubMed  Google Scholar 

  29. Pawelec G et al (2010) Immunosenescence and cytomegalovirus: where do we stand after a decade? Immun Ageing 7:13

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Biagi E et al (2010) Through ageing, and beyond: gut microbiota and inflammatory status in seniors and centenarians. PLoS One 5:e10667

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Morrisette-Thomas V et al (2014) Inflamm-aging does not simply reflect increases in pro-inflammatory markers. Mech Ageing Dev 139:49–57

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. van Duin D et al (2007) Age-associated defect in human TLR-1/2 function. J Immunol 178:970–975

    Article  PubMed  Google Scholar 

  33. Nyugen J et al (2010) Impaired functions of peripheral blood monocyte subpopulations in aged humans. J Clin Immunol 30:806–813

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Fagiolo U et al (1993) Increased cytokine production in mononuclear cells of healthy elderly people. Eur J Immunol 23:2375–2378

    Article  CAS  PubMed  Google Scholar 

  35. Simpson JL et al (2013) Influence of age, past smoking, and disease severity on TLR2, neutrophilic inflammation, and MMP-9 levels in COPD. Mediat Inflamm 2013:462934

    Article  CAS  Google Scholar 

  36. Fulop T et al (2004) Signal transduction and functional changes in neutrophils with aging. Aging Cell 3:217–226

    Article  CAS  Google Scholar 

  37. Murciano C et al (2007) In vitro response to Candida albicans in cultures of whole human blood from young and aged donors. FEMS Immunol Med Microbiol 51:327–335

    Article  CAS  PubMed  Google Scholar 

  38. Renshaw M et al (2002) Cutting edge: impaired Toll-like receptor expression and function in aging. J Immunol 169:4697–4701

    Article  CAS  PubMed  Google Scholar 

  39. Boyd AR et al (2012) Age-related defects in TLR2 signaling diminish the cytokine response by alveolar macrophages during murine pneumococcal pneumonia. Exp Gerontol 47:507–518

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Born J et al (1995) Cytokine production and lymphocyte subpopulations in aged humans. An assessment during nocturnal sleep. Mech Ageing Dev 84:113–126

    Article  CAS  PubMed  Google Scholar 

  41. Bruunsgaard H et al (1999) Impaired production of proinflammatory cytokines in response to lipopolysaccharide (LPS) stimulation in elderly humans. Clin Exp Immunol 118:235–241

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Roubenoff R et al (1998) Monocyte cytokine production in an elderly population: effect of age and inflammation. J Gerontol A Biol Sci Med Sci 53:M20–M26

    Article  CAS  PubMed  Google Scholar 

  43. van Duin D et al (2007) Prevaccine determination of the expression of costimulatory B7 molecules in activated monocytes predicts influenza vaccine responses in young and older adults. J Infect Dis 195:1590–1597

    Article  CAS  PubMed  Google Scholar 

  44. Olivieri F et al (2013) Toll like receptor signaling in “inflammaging”: microRNA as new players. Immun Ageing 10:11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Hinojosa E, Boyd AR, Orihuela CJ (2009) Age-associated inflammation and toll-like receptor dysfunction prime the lungs for pneumococcal pneumonia. J Infect Dis 200:546–554

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Rhee C et al (2017) Incidence and trends of sepsis in US hospitals using clinical vs claims data, 2009–2014. JAMA 318:1241–1249

    Article  PubMed  PubMed Central  Google Scholar 

  47. Lopez-Otin C et al (2013) The hallmarks of aging. Cell 153:1194–1217

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

All authors have read the journal’s policy on disclosure of potential conflicts of interest. None of the authors have any financial or personal relationship with organizations that could potentially be perceived as influencing the described research to disclose. All authors have read the journal’s authorship statement and agree to the submission of this paper.

Funding

Funding sources: VA Merit Award (I01CX000434) to TDL; National Institute for Occupational Safety and Health (R01OH008539) to DJR; National Institute on Aging (R01AG053553) to KLB.

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Authors and Affiliations

  1. Division of Pulmonary, Critical Care, Sleep and Allergy, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, 68198-5910, USA

    Kristina L. Bailey, Art J. Heires, Dawn M. Katafiasz, Debra J. Romberger & Tricia D. LeVan

  2. Department of Biostatistics, University of Nebraska Medical Center, Omaha, NE, 68198, USA

    Lynette M. Smith

  3. VA Nebraska-Western Iowa Health Care System, Omaha, NE, 68105, USA

    Kristina L. Bailey, Art J. Heires, Debra J. Romberger & Tricia D. LeVan

  4. Department of Epidemiology, University of Nebraska Medical Center, Omaha, NE, 68198, USA

    Tricia D. LeVan

Authors
  1. Kristina L. Bailey
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  2. Lynette M. Smith
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  4. Dawn M. Katafiasz
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Correspondence to Kristina L. Bailey.

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This project was conducted with the approval of the internal review board from the VA Nebraska Western Iowa Health Care System.

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Bailey, K.L., Smith, L.M., Heires, A.J. et al. Aging leads to dysfunctional innate immune responses to TLR2 and TLR4 agonists. Aging Clin Exp Res 31, 1185–1193 (2019). https://doi.org/10.1007/s40520-018-1064-0

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  • DOI: https://doi.org/10.1007/s40520-018-1064-0

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