Age-Associated Defect in Human TLR-1/2 Function
Abstract
The effects of aging on human TLR function remain incompletely understood. We assessed TLR function and expression in peripheral blood monocytes from 159 subjects in 2 age categories, 21–30 and >65 years of age, using a multivariable mixed effect model. Using flow cytometry to assess TLR-induced cytokine production, we observed a substantial, highly significant defect in TLR1/2-induced TNF-α (p = 0.0003) and IL-6 (p < 0.0001) production, in older adults compared with young controls. In contrast to findings in aged mice, other TLR (including TLR2/6)-induced cytokine production appeared largely intact. These differences were highly significant even after correcting for covariates including gender, race, medications, and comorbidities. This defect in TLR1/2 signaling may result from alterations in baseline TLR1 surface expression, which was decreased by 36% in older adults (p < 0.0001), whereas TLR2 surface expression was unaffected by aging. Production of IL-6 (p < 0.0001) and TNF-α (p = 0.003) after stimulation by N-palmitoyl-S-[2,3-bis(palmitoyloxy)-(2R,S)-propyl]-Cys-[S]-Ser1-[S]-Lys(4) trihydrochloride was strongly associated with TLR1 surface expression. Diminished TLR1/2 signaling may contribute to the increased infection-related morbidity and mortality and the impaired vaccine responses observed in aging humans.
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Many immune cell subsets become hyporesponsive to acute challenges with age.
“Thus, many immune cell subsets become hyporesponsive to acute challenges as we age17,19-25.”
From SARS-CoV-2, COVID-19 and the aging immune system (2021) · cites this paper as [24]
In human monocytes, TNF-α and IL-6 synthesis after TLR1/2 engagement is severely reduced, while TNF-α release after TLR4 stimulation is increased.
“The synthesis of TNF-α and IL-6 after TLR1/2 engagement, for example, is severely reduced in human monocytes, while release of TNF-α upon TLR4 stimulation is increased [48].”
From Aging of the immune system: Focus on inflammation and vaccination (2016) · cites this paper as [48]
The lower TLR1/2-stimulated cytokine production in aged monocytes is thought to result from decreased TLR1 expression on monocytes of older individuals.
“this is believed to be due to a reduced expression of TLR1 on the monocytes of older individuals (129, 135).”
From The impact of ageing on monocytes and macrophages (2021) · cites this paper as [135]
When stimulated with TLR1/2 agonists such as PamCy3, monocytes from older people produce less TNFα and IL-6 than monocytes from young people.
“When monocytes are stimulated with TLR1/2 stimuli such as PamCy3 there reduced production of TNFα and IL-6 from aged monocytes as compared to young”
From The impact of ageing on monocytes and macrophages (2021) · cites this paper as [135]
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- Authors
- van Duin, D., Mohanty, S., Thomas, V., Ginter, S., Montgomery, R. R., Fikrig, E., Allore, H. G., Medzhitov, R., & Shaw, A. C.
- Affiliations
- Infectious Diseases, Yale University School of Medicine , New Haven, CT 06520
- Yale University (US)
- ORCID
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2007-01
- Volume
- 178
- Issue
- 2
- Pages
- 970-975
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W2152536923
- Cited by
- 352
- References
- 35
- Citations by year
- 2026: 7 · 2025: 14 · 2024: 9 · 2023: 23 · 2022: 16 · 2021: 30 · 2020: 16 · 2019: 10 · 2018: 24 · 2017: 20 · 2016: 19 · 2015: 26 · 2014: 22 · 2013: 24 · 2012: 19
- FWCI
- 7.06
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (n01ai50031-6-0-1)
- National Institute on Aging (P30AG021342)
- National Institute of Allergy and Infectious Diseases (AI053279, N01-AI-50031, R01AI053279, T32AI007517)
- National Center for Research Resources (K12 RR 17594, K12RR017594)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Keywords
- aging, TLR2, monocytes, TNF-α, interleukin-6, cytokine production, older adults, innate immunity, infection susceptibility, vaccine response
- MeSH terms
- Adult, Aged, Aging, Cell Membrane, Female, Humans, Male, Middle Aged, Tumor Necrosis Factor-alpha, Interleukin-6, Toll-Like Receptor 1, Toll-Like Receptor 2
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