Enhancement of cutaneous immunity during ageing by blocking p38 MAPkinase induced inflammation

Milica Vukmanovic-Stejic; Emma S Chambers; Mayte Suarez- Farinas; 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 Krueger; Arne N Akbar

doi:10.1016/j.jaci.2017.10.032

Enhancement of cutaneous immunity during ageing by blocking p38 MAPkinase induced inflammation

Milica Vukmanovic-Stejic, Emma S Chambers, Mayte Suarez- Farinas, 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 Krueger, Arne N Akbar

Royal (Dick) School of Veterinary Studies

Research output: Contribution to journal › Article › peer-review

Abstract

BACKGROUND: Immunity declines with age that leads to re-activation of varicella zoster virus (VZV). In humans, age associated immune changes are usually measured in blood leukocytes however this may 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 ageing.

METHODS: We assessed cutaneous immunity by the extent of erythema and induration after intradermal VZV antigen injection. We also performed immune histology and transcriptomic analyses on skin biopsies taken from the site of challenge in young (<40 yrs) and old (>65 yrs) subjects.

RESULTS: Old humans 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 to young subjects. This was associated with elevated sterile inflammation in the skin in the same subjects, related to p38 MAPK-related pro-inflammatory cytokine production (p <0.0007). We inhibited systemic inflammation in old subjects by pre-treatment with an oral small molecule p38 MAP kinase inhibitor (Losmapimod), which reduced both serum C reactive protein (CRP) and peripheral blood monocyte secretion of IL-6 and TNF-α. In contrast, cutaneous responses to VZV antigen challenge was significantly increased in the same individuals (p <0.0006).

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 may be utilized to promote vaccine efficacy and the treatment of infections and malignancy during ageing.

Original language	English
Pages (from-to)	844-856
Journal	Journal of Allergy and Clinical Immunology
Volume	142
Issue number	3
Early online date	17 Nov 2017
DOIs	https://doi.org/10.1016/j.jaci.2017.10.032
Publication status	Published - Sept 2018

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Journal Article

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10.1016/j.jaci.2017.10.032

1-s2.0-S0091674917317669-main
Open access funded by MRC
Accepted author manuscript, 3.52 MBLicence: CC BY

MICA enhancing immunity in older humans by targeting the p38 MAPkinase signalling pathway and vitamin D supplementation
Mabbott, N. & Freeman, T.
Other
30/04/15 → 15/06/19
Project: Research

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Vukmanovic-Stejic, M., Chambers, E. S., Farinas, M. S., 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., & Akbar, A. N. (2018). Enhancement of cutaneous immunity during ageing by blocking p38 MAPkinase induced inflammation. Journal of Allergy and Clinical Immunology, 142(3), 844-856. https://doi.org/10.1016/j.jaci.2017.10.032

@article{d32948d40aa94cdf82d4adcdb704886b,

title = "Enhancement of cutaneous immunity during ageing by blocking p38 MAPkinase induced inflammation",

abstract = "BACKGROUND: Immunity declines with age that leads to re-activation of varicella zoster virus (VZV). In humans, age associated immune changes are usually measured in blood leukocytes however this may 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 ageing.METHODS: We assessed cutaneous immunity by the extent of erythema and induration after intradermal VZV antigen injection. We also performed immune histology and transcriptomic analyses on skin biopsies taken from the site of challenge in young (<40 yrs) and old (>65 yrs) subjects.RESULTS: Old humans 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 to young subjects. This was associated with elevated sterile inflammation in the skin in the same subjects, related to p38 MAPK-related pro-inflammatory cytokine production (p <0.0007). We inhibited systemic inflammation in old subjects by pre-treatment with an oral small molecule p38 MAP kinase inhibitor (Losmapimod), which reduced both serum C reactive protein (CRP) and peripheral blood monocyte secretion of IL-6 and TNF-α. In contrast, cutaneous responses to VZV antigen challenge was significantly increased in the same individuals (p <0.0006).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 may be utilized to promote vaccine efficacy and the treatment of infections and malignancy during ageing.",

keywords = "Journal Article",

author = "Milica Vukmanovic-Stejic and Chambers, {Emma S} and Farinas, {Mayte Suarez-} and Daisy Sandhu and Judilyn Fuentes-Duculan and Neil Patel and Elaine Agius and Lacy, {Katie E} and Turner, {Carolin T} and Anis Larbi and Veronique Birault and Mahdad Noursadeghi and Mabbott, {Neil A} and Rustin, {Malcolm H A} and James Krueger and Akbar, {Arne N}",

note = "Copyright {\textcopyright} 2017. Published by Elsevier Inc.",

year = "2018",

month = sep,

doi = "10.1016/j.jaci.2017.10.032",

language = "English",

volume = "142",

pages = "844--856",

journal = "Journal of Allergy and Clinical Immunology",

issn = "0091-6749",

publisher = "Mosby ",

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Vukmanovic-Stejic, M, Chambers, ES, Farinas, MS, Sandhu, D, Fuentes-Duculan, J, Patel, N, Agius, E, Lacy, KE, Turner, CT, Larbi, A, Birault, V, Noursadeghi, M, Mabbott, NA, Rustin, MHA, Krueger, J & Akbar, AN 2018, 'Enhancement of cutaneous immunity during ageing by blocking p38 MAPkinase induced inflammation', Journal of Allergy and Clinical Immunology, vol. 142, no. 3, pp. 844-856. https://doi.org/10.1016/j.jaci.2017.10.032

TY - JOUR

T1 - Enhancement of cutaneous immunity during ageing by blocking p38 MAPkinase induced inflammation

AU - Vukmanovic-Stejic, Milica

AU - Chambers, Emma S

AU - Farinas, Mayte Suarez-

AU - Sandhu, Daisy

AU - Fuentes-Duculan, Judilyn

AU - Patel, Neil

AU - Agius, Elaine

AU - Lacy, Katie E

AU - Turner, Carolin T

AU - Larbi, Anis

AU - Birault, Veronique

AU - Noursadeghi, Mahdad

AU - Mabbott, Neil A

AU - Rustin, Malcolm H A

AU - Krueger, James

AU - Akbar, Arne N

PY - 2018/9

Y1 - 2018/9

N2 - BACKGROUND: Immunity declines with age that leads to re-activation of varicella zoster virus (VZV). In humans, age associated immune changes are usually measured in blood leukocytes however this may 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 ageing.METHODS: We assessed cutaneous immunity by the extent of erythema and induration after intradermal VZV antigen injection. We also performed immune histology and transcriptomic analyses on skin biopsies taken from the site of challenge in young (<40 yrs) and old (>65 yrs) subjects.RESULTS: Old humans 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 to young subjects. This was associated with elevated sterile inflammation in the skin in the same subjects, related to p38 MAPK-related pro-inflammatory cytokine production (p <0.0007). We inhibited systemic inflammation in old subjects by pre-treatment with an oral small molecule p38 MAP kinase inhibitor (Losmapimod), which reduced both serum C reactive protein (CRP) and peripheral blood monocyte secretion of IL-6 and TNF-α. In contrast, cutaneous responses to VZV antigen challenge was significantly increased in the same individuals (p <0.0006).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 may be utilized to promote vaccine efficacy and the treatment of infections and malignancy during ageing.

AB - BACKGROUND: Immunity declines with age that leads to re-activation of varicella zoster virus (VZV). In humans, age associated immune changes are usually measured in blood leukocytes however this may 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 ageing.METHODS: We assessed cutaneous immunity by the extent of erythema and induration after intradermal VZV antigen injection. We also performed immune histology and transcriptomic analyses on skin biopsies taken from the site of challenge in young (<40 yrs) and old (>65 yrs) subjects.RESULTS: Old humans 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 to young subjects. This was associated with elevated sterile inflammation in the skin in the same subjects, related to p38 MAPK-related pro-inflammatory cytokine production (p <0.0007). We inhibited systemic inflammation in old subjects by pre-treatment with an oral small molecule p38 MAP kinase inhibitor (Losmapimod), which reduced both serum C reactive protein (CRP) and peripheral blood monocyte secretion of IL-6 and TNF-α. In contrast, cutaneous responses to VZV antigen challenge was significantly increased in the same individuals (p <0.0006).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 may be utilized to promote vaccine efficacy and the treatment of infections and malignancy during ageing.

KW - Journal Article

U2 - 10.1016/j.jaci.2017.10.032

DO - 10.1016/j.jaci.2017.10.032

M3 - Article

C2 - 29155150

SN - 0091-6749

VL - 142

SP - 844

EP - 856

JO - Journal of Allergy and Clinical Immunology

JF - Journal of Allergy and Clinical Immunology

IS - 3

ER -

Enhancement of cutaneous immunity during ageing by blocking p38 MAPkinase induced inflammation

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MICA enhancing immunity in older humans by targeting the p38 MAPkinase signalling pathway and vitamin D supplementation

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