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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-?. 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.

SUBMITTER: Vukmanovic-Stejic M

PROVIDER: S-EPMC6127037 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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

Vukmanovic-Stejic Milica M Chambers Emma S ES Suárez-Fariñas Mayte M Sandhu Daisy D Fuentes-Duculan Judilyn J Patel Neil N Agius Elaine E Lacy Katie E KE Turner Carolin T CT Larbi Anis A Birault Veronique V Noursadeghi Mahdad M Mabbott Neil A NA Rustin Malcolm H A MHA Krueger James G JG Akbar Arne N AN

The Journal of allergy and clinical immunology 20171117 3

<h4>Background</h4>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.<h4>Objectives</h4>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.<h4>Methods</h4>We assessed cutaneous immuni ...[more]

PMID: 29155150

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Project description:Aortic stiffening commonly occurs in hypertension and further elevates systolic pressure. Hypertension is also associated with vascular inflammation and increased mechanical stretch. The interplay between inflammation, mechanical stretch, and aortic stiffening in hypertension remains undefined.Our aim was to determine the role of inflammation and mechanical stretch in aortic stiffening.Chronic angiotensin II infusion caused marked aortic adventitial collagen deposition, as quantified by Masson trichrome blue staining and biochemically by hydroxyproline content, in wild-type but not in recombination activating gene-1-deficient mice. Aortic compliance, defined by ex vivo measurements of stress-strain curves, was reduced by chronic angiotensin II infusion in wild-type mice (P<0.01) but not in recombination activating gene-1-deficient mice (P<0.05). Adoptive transfer of T-cells to recombination activating gene-1-deficient mice restored aortic collagen deposition and stiffness to values observed in wild-type mice. Mice lacking the T-cell-derived cytokine interleukin 17a were also protected against aortic stiffening. In additional studies, we found that blood pressure normalization by treatment with hydralazine and hydrochlorothiazide prevented angiotensin II-induced vascular T-cell infiltration, aortic stiffening, and collagen deposition. Finally, we found that mechanical stretch induces the expression of collagen 1?1, 3?1, and 5a1 in cultured aortic fibroblasts in a p38 mitogen-activated protein kinase-dependent fashion, and that inhibition of p38 prevented angiotensin II-induced aortic stiffening in vivo. Interleukin 17a also induced collagen 3a1 expression via the activation of p38 mitogen-activated protein kinase.Our data define a pathway in which inflammation and mechanical stretch lead to vascular inflammation that promotes collagen deposition. The resultant increase in aortic stiffness likely further worsens systolic hypertension and its attendant end-organ damage.

Dataset Information

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

Publications

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

Similar Datasets

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