Enhancement of cutaneous immunity during aging by blocking p38 mitogen-activated protein (MAP) kinase–induced inflammation - 06/09/18
, Emma S. Chambers, PhD a, ∗, Mayte Suárez-Fariñas, PhD b, ∗, Daisy Sandhu, MD a, c, Judilyn Fuentes-Duculan, MD b, Neil Patel, MRCP a, c, Elaine Agius, MD, PhD a, c, Katie E. Lacy, MD, PhD a, c, d, Carolin T. Turner, PhD a, Anis Larbi, PhD e, Veronique Birault, PhD f, Mahdad Noursadeghi, MD, PhD a, Neil A. Mabbott, PhD g, Malcolm H.A. Rustin, MD c, James G. Krueger, MD, PhD b, Arne N. Akbar, PhD a, ⁎ 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.
Le texte complet de cet article est disponible en PDF.Graphical abstract |
Key words : Aging, p38 mitogen-activated protein kinase, varicella zoster virus, inflammation
Abbreviations used : CBA, CRP, DC, DEG, MAP, TRM, VZV
Plan
| Supported by the Medical Research Council (MRC) Grand Challenge in Experimental Medicine (MICA) Grant (MR/M003833/1 to A.N.A., M.V.-S., V.B., N.A.M., and M.N.), an MRC New Investigator award (G0901102 to M.V.-S.), Dermatrust (to A.N.A.), the British Skin Foundation (BSF5012 to A.N.A.), and the National Institute for Health Research University College London Hospitals Biomedical Research Centre. |
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| Disclosure of potential conflict of interest: M. Suárez-Fariñas serves as a consultant for NWA, receives grant support from Pfizer, and receives travel support from DBV. A. N. Akbar receives payment for lectures from Jansen and Jansen LTD. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 142 - N° 3
P. 844-856 - septembre 2018 Retour au numéro
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