TREM-2 promotes macrophage survival and lung disease after respiratory viral infection
Open accessAbstract
Viral infections and type 2 immune responses are thought to be critical for the development of chronic respiratory disease, but the link between these events needs to be better defined. Here, we study a mouse model in which infection with a mouse parainfluenza virus known as Sendai virus (SeV) leads to long-term activation of innate immune cells that drive IL-13-dependent lung disease. We find that chronic postviral disease (signified by formation of excess airway mucus and accumulation of M2-differentiating lung macrophages) requires macrophage expression of triggering receptor expressed on myeloid cells-2 (TREM-2). Analysis of mechanism shows that viral replication increases lung macrophage levels of intracellular and cell surface TREM-2, and this action prevents macrophage apoptosis that would otherwise occur during the acute illness (5-12 d after inoculation). However, the largest increases in TREM-2 levels are found as the soluble form (sTREM-2) long after clearance of infection (49 d after inoculation). At this time, IL-13 and the adapter protein DAP12 promote TREM-2 cleavage to sTREM-2 that is unexpectedly active in preventing macrophage apoptosis. The results thereby define an unprecedented mechanism for a feed-forward expansion of lung macrophages (with IL-13 production and consequent M2 differentiation) that further explains how acute infection leads to chronic inflammatory disease.
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Trem2 knockdown decreasing survival and altering metabolism of microglia is consistent with previous studies.
“The knockdown of Trem2 decreasing survival and altering the metabolism of microglia is consistent with previous studies (35,38–40,56,57).”
From <i>Trem2</i> promotes anti-inflammatory responses in microglia and is suppressed under pro-inflammatory conditions (2020) · cites this paper as [56]
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- Authors
- Wu, K., Byers, D. E., Jin, X., Agapov, E., Alexander-Brett, J., Patel, A. C., Cella, M., Gilfilan, S., Colonna, M., Kober, D. L., Brett, T. J., & Holtzman, M. J.
- Affiliations
- Washington University in St. Louis (US)
- Pulmonary and Critical Care Medicine, Department of Medicine 1 , 2 , 3 , 4 , and 5
- Corresponding author
- Holtzman, Michael J.
- ORCID
- Venue
- Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2015-04-20
- Volume
- 212
- Issue
- 5
- Pages
- 681-697
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC4419356
- OpenAlex
- W2111240640
- Cited by
- 207
- References
- 41
- Citations by year
- 2026: 11 · 2025: 17 · 2024: 19 · 2023: 23 · 2022: 36 · 2021: 24 · 2020: 22 · 2019: 8 · 2018: 14 · 2017: 16 · 2016: 11 · 2015: 4
- FWCI
- 7.33
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- cc-by-nc-sa
- Locations
- The Journal of Experimental Medicine (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01HL119813, P01HL029594, R01HL073159, R01HL121791, P50HL084922, T32HL007317)
- National Institute of Allergy and Infectious Diseases (U19-AI07048, U19AI070489)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Inflammation biomarkers and pathways
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Health Sciences › Medicine › Physiology › Asthma and respiratory diseases
- Keywords
- TREM2, macrophage survival, macrophage apoptosis, Sendai virus, respiratory viral infections, IL-13, DAP12, M2 macrophages, Th2 immune response, airway mucus hypersecretion, innate immune activation
- MeSH terms
- Animals, Cell Survival, Immunity, Innate, Lung Diseases, Membrane Glycoproteins, Respirovirus Infections, Receptors, Immunologic, Virus Replication, Macrophages, Alveolar, Apoptosis, Mice, Knockout, Interleukin-13, Sendai virus, Mice
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