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      Plasmacytoid dendritic cell and myeloid dendritic cell function in ageing: A comparison between elderly and young adult women

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          Abstract

          Ageing is associated with a changing immune system, leading to inflammageing (increased levels of inflammation markers in serum) and immunosenescence (reduced immune cells and reduced responses towards pathogens). This results in reduced vaccination responses and increased infections in elderly. Much is known about the adaptive immune system upon ageing, but less is known about the innate immune system. Therefore, the aim of this study was to compare innate immune function of Toll like receptor (TLR)-mediated responses between elderly and young adult women.

          To this end, elderly and young adult women were compared to study the effect of ageing on the relative prevalence and reactivity to TLR-mediated responses of myeloid- and plasmacytoid dendritic cells (mDC, pDC). In addition, TLR expression and inflammatory markers in serum were investigated. Elderly women had reduced numbers of circulating pDCs. In addition, pDCs and mDCs of elderly women responded differently towards TLR stimulation, especially TLR7/8 mediated stimulation was reduced, compared to young adults. In serum, markers involved in inflammation were generally increased in elderly. In conclusion, this study confirms and extends the knowledge about immunosenescence and inflammageing on innate immunity in elderly women.

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          Most cited references43

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          The X-files in immunity: sex-based differences predispose immune responses

          Sex-based differences in immune responses can influence the susceptibility to autoimmune and infectious diseases and the efficacy of therapeutic drugs. In this Perspective, Eleanor Fish discusses factors, such as X-linked genes, hormones and societal context, that underlie disparate immune responses in men and women.
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            Inflammatory markers in population studies of aging.

            To review findings from major epidemiologic studies regarding risk factors for and consequences of elevated markers of inflammation in older adults. Most large, current epidemiologic studies of older adults have measured serum interleukin-6 (IL-6), C-reactive protein (CRP) and tumor necrosis factor alpha (TNF-alpha) and some studies also include more extensive batteries of measures including soluble receptors. There are few defined risk factors for the modest elevations in inflammatory markers seen with aging. These include visceral adiposity, lower sex steroid hormones, smoking, depression and periodontal disease. Of the markers assessed, IL-6 is most robustly associated with incident disease, disability and mortality. Though correlated with age, the etiology of elevated inflammatory markers remains incompletely defined. Inflammation, especially IL-6 may be a common cause of multiple age-related diseases or a final common pathway by which disease leads to disability and adverse outcomes in older adults. Future research targeting inflammation should examine these pathways. Copyright © 2011. Published by Elsevier B.V.
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              Age-associated decrease in TLR function in primary human dendritic cells predicts influenza vaccine response.

              We evaluated TLR function in primary human dendritic cells (DCs) from 104 young (age 21-30 y) and older (> or =65 y) individuals. We used multicolor flow cytometry and intracellular cytokine staining of myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) and found substantial decreases in older compared with young individuals in TNF-alpha, IL-6, and/or IL-12 (p40) production in mDCs and in TNF-alpha and IFN-alpha production in pDCs in response to TLR1/2, TLR2/6, TLR3, TLR5, and TLR8 engagement in mDCs and TLR7 and TLR9 in pDCs. These differences were highly significant after adjustment for heterogeneity between young and older groups (e.g., gender, race, body mass index, number of comorbid medical conditions) using mixed-effect statistical modeling. Studies of surface and intracellular expression of TLR proteins and of TLR gene expression in purified mDCs and pDCs revealed potential contributions for both transcriptional and posttranscriptional mechanisms in these age-associated effects. Moreover, intracellular cytokine production in the absence of TLR ligand stimulation was elevated in cells from older compared with young individuals, suggesting a dysregulation of cytokine production that may limit further activation by TLR engagement. Our results provide evidence for immunosenescence in DCs; notably, defects in cytokine production were strongly associated with poor Ab response to influenza immunization, a functional consequence of impaired TLR function in the aging innate immune response.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: ValidationRole: VisualizationRole: Writing – original draft
                Role: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: Methodology
                Role: InvestigationRole: MethodologyRole: Project administration
                Role: Formal analysisRole: InvestigationRole: MethodologyRole: Visualization
                Role: InvestigationRole: MethodologyRole: SupervisionRole: Writing – review & editing
                Role: SupervisionRole: Writing – review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: Writing – review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                12 December 2019
                2019
                : 14
                : 12
                : e0225825
                Affiliations
                [1 ] Cell Biology and Immunology, Wageningen University, Wageningen, The Netherlands
                [2 ] Human Nutrition, Wageningen University, Wageningen, The Netherlands
                [3 ] NIZO Food research, Ede, The Netherlands
                [4 ] FrieslandCampina, Amersfoort, The Netherlands
                Emory University School of Medicine, UNITED STATES
                Author notes

                Competing Interests: JvN is employed by FrieslandCampina and is professor at Wageningen University. MvS, OP, EFV, EvH received research funding from FrieslandCampina to execute the study. HFB, BM, SB and HS have no conflict of interest. This does not alter our adherence to PLOS ONE policies on sharing data and materials. All authors concur with submission of this work and the manuscript has not been submitted to another journal.

                Author information
                http://orcid.org/0000-0002-8695-9030
                Article
                PONE-D-19-24628
                10.1371/journal.pone.0225825
                6907850
                31830086
                46e6c105-172c-40e0-b235-5a5b3a2c9bf3
                © 2019 Splunter et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 1 September 2019
                : 12 November 2019
                Page count
                Figures: 4, Tables: 3, Pages: 19
                Funding
                Funded by: FrieslandCampina
                Award Recipient :
                Part of this study was financed by FrieslandCampina. The funder provided support in the form of salaries for authors [JvN], but did not have any additional role in the design of this study, data collection and analysis, decision to publish, or preparation of the manuscript. The funder funded the clinical study published elsewhere (Bovine Lactoferrin Enhances TLR7-Mediated Responses in Plasmacytoid Dendritic Cells in Elderly Women: Results From a Nutritional Intervention Study With Bovine Lactoferrin, GOS and Vitamin D. van Splunter M, Perdijk O, Fick-Brinkhof H, Feitsma AL, Floris-Vollenbroek EG, Meijer B, Brugman S, Savelkoul HFJ, van Hoffen E, van Neerven RJJ. Front Immunol. 2018 Nov 20;9:2677. doi: 10.3389/fimmu.2018.02677. eCollection 2018). The additional work in the current publication does not include any links to dairy ingredients, and was designed and performed independently from funder, through the university affiliation of JvN. The specific roles of these authors are articulated in the ‘author contributions’ section.
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