Blocking elevated p38 MAPK restores efferocytosis and inflammatory resolution in the elderly
- 6 April 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Immunology
- Vol. 21 (6), 615-625
- https://doi.org/10.1038/s41590-020-0646-0
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.Keywords
Funding Information
- RCUK | Medical Research Council (MR/J006610/1, MR/M003833/1)
- RCUK | MRC | Medical Research Foundation (MR/J006610/1, MR/M003833/1, MR/M003833/1)
This publication has 70 references indexed in Scilit:
- p38 MAPK- and Akt-mediated p300 phosphorylation regulates its degradation to facilitate nucleotide excision repairNucleic Acids Research, 2012
- Macrophage plasticity and polarization: in vivo veritasJCI Insight, 2012
- Validation of the cantharidin-induced skin blister as anin vivomodel of inflammationBritish Journal of Clinical Pharmacology, 2011
- LXRα Regulates Macrophage Arginase 1 Through PU.1 and Interferon Regulatory Factor 8Circulation Research, 2011
- Phosphatidylserine receptor Tim-4 is essential for the maintenance of the homeostatic state of resident peritoneal macrophagesProceedings of the National Academy of Sciences of the United States of America, 2010
- Macrophage Dysfunction Impairs Resolution of Inflammation in the Wounds of Diabetic MicePLOS ONE, 2010
- A novel role for c-Src and STAT3 in apoptotic cell–mediated MerTK-dependent immunoregulation of dendritic cellsBlood, 2009
- Identification of Tim4 as a phosphatidylserine receptorNature, 2007
- Alternative activation of macrophagesNature Reviews Immunology, 2003
- Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-beta, PGE2, and PAF.JCI Insight, 1998