Enhancement of cutaneous immunity during aging by blocking p38 mitogen-activated protein (MAP) kinase-induced inflammation.

Abstract

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:

Old human subjects exhibited decreased erythema and induration, CD4+ and CD8+ 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.

• Authors: Milica Vukmanovic-Stejic, Emma S Chambers, Mayte Suárez-Fariñas, Daisy Sandhu, Judilyn Fuentes-Duculan, Neil Patel, Elaine Agius, Katie E Lacy, Carolin T Turner, Anis Larbi, Veronique Birault, Mahdad Noursadeghi, Neil A Mabbott, Malcolm H A Rustin, James G Krueger, Arne N Akbar
• Journal: The Journal of allergy and clinical immunology (J Allergy Clin Immunol) Vol. 142 Issue 3 Pg. 844-856 (09 2018) ISSN: 1097-6825 [Electronic] United States
• PMID: 29155150 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Antigens, Viral
• IL6 protein, human
• Interleukin-6
• Tumor Necrosis Factor-alpha
• C-Reactive Protein
• p38 Mitogen-Activated Protein Kinases

Topics

• Adult
• Aged
• Aged, 80 and over
• Aging (blood, immunology)
• Antigens, Viral (immunology)
• C-Reactive Protein (analysis)
• CD4-Positive T-Lymphocytes (immunology)
• CD8-Positive T-Lymphocytes (immunology)
• Female
• Herpesvirus 3, Human (immunology)
• Humans
• Inflammation (blood, immunology)
• Interleukin-6 (blood)
• Male
• Middle Aged
• Skin (immunology)
• Tumor Necrosis Factor-alpha (blood)
• Young Adult
• p38 Mitogen-Activated Protein Kinases (immunology)