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Blocking elevated p38 MAPK restores efferocytosis and inflammatory resolution in the elderly
Open accessAbstract
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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“This defect in resolution was due to lower expression of expression of T cell immunoglobulin mucin receptor-4 (TIM-4), a receptor that recognizes apoptotic cells, and a subsequent failure to phagocytose apoptotic neutrophils as compared to younger monocytes (33).”
From The impact of ageing on monocytes and macrophages (2021) · cites this paper as [33]
In the citing paper
“Ultimately this kind of mechanism, of failed resolution, might underlie chronic inflammation such as that seen in aged people (33).”
From The impact of ageing on monocytes and macrophages (2021) · cites this paper as [33]
In the citing paper
“Mononuclear phagocytes, consisting of monocytes and macrophages, were unable to engulf apoptotic immune cells following an inflammatory insult.”
From The impact of ageing on monocytes and macrophages (2021) · cites this paper as [33]
In the citing paper
“and thus identifies a therapeutic target for improving monocyte function in older people (33).”
From The impact of ageing on monocytes and macrophages (2021) · cites this paper as [33]
In the citing paper
“Interestingly this defect in resolution in the old could be reversed by pre-treatment with a p38-MAP Kinase inhibitor (Losmapimod)”
From The impact of ageing on monocytes and macrophages (2021) · cites this paper as [33]
In the citing paper
“Recently we have shown that mononuclear phagocytes, presumed to be inflammatory monocytes, from older adults, recruited to a site of tissue damage fail to resolve inflammation as effectively as younger monocytes (33).”
From The impact of ageing on monocytes and macrophages (2021) · cites this paper as [33]
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Metadata
- 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
- Venue
- Nature Immunology
- Published
- 2020-04-06
- Volume
- 21
- Issue
- 6
- Pages
- 615-625
- ISSN
- 1529-2908 (ISSN-L)
- 1529-2916
- 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
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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