Enhancement of cutaneous immunity during aging by blocking p38 mitogen-activated protein (MAP) kinase-induced inflammation
Open accessAbstract
BACKGROUND: Immunity decreases with age, which leads to reactivation of varicella zoster virus (VZV). In human subjects age-associated immune changes are usually measured in blood leukocytes; however, this might not reflect alterations in tissue-specific immunity. OBJECTIVES: We used a VZV antigen challenge system in the skin to investigate changes in tissue-specific mechanisms involved in the decreased response to this virus during aging. METHODS: We assessed cutaneous immunity based on the extent of erythema and induration after intradermal VZV antigen injection. We also performed immune histology and transcriptomic analyses on skin biopsy specimens taken from the challenge site in young (<40 years) and old (>65 years) subjects. RESULTS: T-cell infiltration, and attenuated global gene activation at the site of cutaneous VZV antigen challenge compared with young subjects. This was associated with increased sterile inflammation in the skin in the same subjects related to p38 mitogen-activated protein kinase-related proinflammatory cytokine production (P < .0007). We inhibited systemic inflammation in old subjects by means of pretreatment with an oral small-molecule p38 mitogen-activated protein kinase inhibitor (Losmapimod; GlaxoSmithKline, Brentford, United Kingdom), which reduced both serum C-reactive protein levels and peripheral blood monocyte secretion of IL-6 and TNF-α. In contrast, cutaneous responses to VZV antigen challenge were increased significantly in the same subjects (P < .0003). CONCLUSION: Excessive inflammation in the skin early after antigen challenge retards antigen-specific immunity. However, this can be reversed by inhibition of inflammatory cytokine production that can be used to promote vaccine efficacy and the treatment of infections and malignancy during aging.
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This increased non-specific inflammation is inversely correlated with antigen-specific cutaneous immunity.
“This increased non-specific inflammation negatively correlated with antigen-specific cutaneous immunity (26).”
From The impact of ageing on monocytes and macrophages (2021) · cites this paper as [26]
Older people show increased monocyte recruitment to a needle challenge site, whether air, saline or antigen is injected.
“In addition, we have shown that older people have an increased recruitment of monocytes to a site of needle challenge (air, saline or antigen) (26,141).”
From The impact of ageing on monocytes and macrophages (2021) · cites this paper as [26]
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- Authors
- Vukmanovic-Stejic, M., Chambers, E. S., Suárez-Fariñas, M., Sandhu, D., Fuentes-Duculan, J., Patel, N., Agius, E., Lacy, K. E., Turner, C. T., Larbi, A., Birault, V., Noursadeghi, M., Mabbott, N. A., Rustin, M. H. A., Krueger, J. G., & Akbar, A. N.
- Affiliations
- University College London (GB)
- The Royal Free Hospital (GB)
- Guy's Hospital (GB)
- Agency for Science, Technology and Research (SG)
- Roslin Institute (GB)
- Rockefeller University (US)
- Corresponding author
- Akbar, Arne N.
- ORCID
- Venue
- Journal of Allergy and Clinical Immunology
- Publisher
- Elsevier BV
- Published
- 2018-09
- Volume
- 142
- Issue
- 3
- Pages
- 844-856
- ISSN
- 0091-6749 (ISSN-L)
- PMC
- PMC6127037
- OpenAlex
- W2768886995
- Cited by
- 103
- References
- 49
- Citations by year
- 2026: 10 · 2025: 12 · 2024: 10 · 2023: 12 · 2022: 13 · 2021: 18 · 2020: 19 · 2019: 6 · 2018: 3
- FWCI
- 5.98
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Allergy and Clinical Immunology (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
- Queen Mary Research Online (Queen Mary University of London) (submittedVersion, cc-by)
- Funders
- Pfizer
- GlaxoSmithKline
- NIHR Biomedical Research Centre, Royal Marsden NHS Foundation Trust/Institute of Cancer Research
- National Institute for Health and Care Research
- British Skin Foundation (MR/M003833/1, BSF5012)
- University College London
- University College London Hospitals NHS Foundation Trust
- Medical Research Council (G0901102, MR/M003833/1, MR/N017749/1)
- Biotechnology and Biological Sciences Research Council (BB/G530433/1, BBS/E/D/10002071, BB/L025302/1, BBS/E/D/20002174, BB/H020519/1)
- Topics
- Health Sciences › Medicine › Epidemiology › Herpesvirus Infections and Treatments
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
- Keywords
- skin immunity, aging, varicella-zoster virus, p38 MAPK, losmapimod, sterile inflammation, T cell infiltration, inflammatory cytokines, interleukin-6, TNF-α, C-reactive protein, skin transcriptomics
- MeSH terms
- Adult, Aged, Aged, 80 and over, Aging, Antigens, Viral, C-Reactive Protein, Female, Humans, Inflammation, Male, Middle Aged, Skin, Tumor Necrosis Factor-alpha, Herpesvirus 3, Human, CD4-Positive T-Lymphocytes, Interleukin-6, CD8-Positive T-Lymphocytes, p38 Mitogen-Activated Protein Kinases, Young Adult
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