Cited by 182Phagocytosis and Immune RegulationImmune Response and InflammationImmune cells in cancer

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Blocking elevated p38 MAPK restores efferocytosis and inflammatory resolution in the elderly

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De Maeyer, Roel P. H., van de Merwe, Rachel C., Louie, Rikah, Bracken, Olivia V., Devine, Oliver P., Goldstein, Daniel R., Uddin, Mohib, Akbar, Arne N., Gilroy, Derek W.·2020·Nature Immunology

DOI 10.1038/s41590-020-0646-0PMC PMC7983074

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Abstract

Increasing age alters innate immune-mediated responses; however, the mechanisms underpinning these changes in humans are not fully understood. Using a human dermal model of acute inflammation, we found that, although inflammatory onset is similar between young and elderly individuals, the resolution phase was substantially impaired in elderly individuals. This arose from a reduction in T cell immunoglobulin mucin receptor-4 (TIM-4), a phosphatidylserine receptor expressed on macrophages that enables the engulfment of apoptotic bodies, so-called efferocytosis. Reduced TIM-4 in elderly individuals was caused by an elevation in macrophage p38 mitogen-activated protein kinase (MAPK) activity. Administering an orally active p38 inhibitor to elderly individuals rescued TIM-4 expression, cleared apoptotic bodies and restored a macrophage resolution phenotype. Thus, inhibiting p38 in elderly individuals rejuvenated their resolution response to be more similar to that of younger people. This is the first resolution defect identified in humans that has been successfully reversed, thereby highlighting the tractability of targeting pro-resolution biology to treat diseases driven by chronic inflammation.

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Authors: De Maeyer, R. P. H., van de Merwe, R. C., Louie, R., Bracken, O. V., Devine, O. P., Goldstein, D. R., Uddin, M., Akbar, A. N., & Gilroy, D. W.
Affiliations: University College London (GB)
University of Michigan (US)
AstraZeneca (Sweden) (SE)
Corresponding author: Gilroy, Derek W.
ORCID: De Maeyer, Roel P. H.
Bracken, Olivia V.
Devine, Oliver P.
Goldstein, Daniel R.
Uddin, Mohib
Akbar, Arne N.
Gilroy, Derek W.
Venue: Nature Immunology
Publisher: Springer Science and Business Media LLC
Published: 2020-04-06
Volume: 21
Issue: 6
Pages: 615-625
ISSN: 1529-2908 (ISSN-L)
1529-2916
DOI: 10.1038/s41590-020-0646-0
PMC: PMC7983074
OpenAlex: W3014659762
Semantic Scholar: d20b763d1d35cbc8254cfdf16cc07adc8e7fcef2
Cited by: 182
References: 71
Citations by year: 2026: 25 · 2025: 38 · 2024: 30 · 2023: 21 · 2022: 26 · 2021: 27 · 2020: 15
FWCI: 7.81
Type: journal article
Language: en
Update notices: correction (2020-04-17)
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springernature.com/gp/researchers/text-and-data-mining (tdm)
www.springernature.com/gp/researchers/text-and-data-mining (vor)
Locations: Nature Immunology (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
UCL Discovery (University College London) (submittedVersion)
Funders: RCUK | Medical Research Council (MR/J006610/1, MR/M003833/1)
Topics: Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
Keywords: p38 MAPK, efferocytosis, inflammation resolution, TIM-4, macrophages, aging, phosphatidylserine receptor, chronic inflammation, innate immunity
MeSH terms: Age Factors, Aged, Animals, Blister, Cantharidin, Humans, Immunity, Innate, Inflammation, Macrophages, Male, Membrane Proteins, Neutrophils, Phagocytosis, Receptors, Cell Surface, Signal Transduction, Gene Expression, Apoptosis, p38 Mitogen-Activated Protein Kinases

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Blocking elevated p38 MAPK restores efferocytosis and inflammatory resolution in the elderly

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