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Cited by 28Interstitial Lung Diseases and Idiopathic Pulmonary FibrosisPulmonary Hypertension Research and TreatmentsSystemic Sclerosis and Related Diseases

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Blockade of TREM2 ameliorates pulmonary inflammation and fibrosis by modulating sphingolipid metabolism

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Gu, Xueqing, Kang, Hanyujie, Cao, Siyu, Tong, Zhaohui, Song, Nan·2025·Translational Research
DOI 10.1016/j.trsl.2024.10.002

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Abstract

Pulmonary fibrosis is a chronic interstitial lung disease involving systemic inflammation and abnormal collagen deposition. Dysregulations in lipid metabolism, such as macrophage-dependent lipid catabolism, have been recognized as critical factors for the development of pulmonary fibrosis. However, little is known about the signaling pathways involved and the key regulators. Here we found that triggering receptor expressed on myeloid cells 2 (TREM2) plays a pivotal role in regulating the lipid handling capacities of pulmonary macrophages and triggering fibrosis. By integrating analysis of single-cell and bulk RNA sequencing data from patients and mice with pulmonary fibrosis, we revealed that pulmonary macrophages consist of heterogeneous populations with distinct pro-fibrotic properties, and found that both sphingolipid metabolism and the expression of chemotaxis-related genes are elevated in fibrotic lungs. TREM2, a sensor recognizing multiple lipid species, is specifically upregulated in a subset of monocyte-derived macrophages. Blockade of TREM2 by conventional/conditional knock-out or soluble TREM2 administration can attenuate bleomycin-induced pulmonary fibrosis. By utilizing scRNA Seq and lipidomics, we found that Trem2 deficiency downregulates the synthesis of various sphingomyelins, and inhibits the expression of chemokines such as Ccl2. Together, our findings not only reveal the alterations in lipidomic profiles and the atlas of pulmonary macrophages during pulmonary fibrosis, but also suggest that targeting TREM2, the crucial regulator affecting both pulmonary sphingolipid metabolism and the chemokines secretion, can benefit pulmonary fibrosis patients in the future.

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Metadata

Authors
Gu, X., Kang, H., Cao, S., Tong, Z., & Song, N.
Affiliations
Capital Medical University (CN)
Corresponding author
  • Tong, Zhaohui
  • Song, Nan
ORCID
Venue
Translational Research
Publisher
Elsevier BV
Published
2025-01
Volume
275
Pages
1-17
ISSN
  • 1878-1810 (ISSN-L)
  • 1931-5244
DOI
10.1016/j.trsl.2024.10.002
OpenAlex
W4403837392
Cited by
28
References
8
Citations by year
2026: 23 · 2025: 5
FWCI
8.13
Type
journal article
Language
en
Open access
Licence
Locations
  • Translational research (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed (publishedVersion)
Funders
  • Natural Science Foundation of Beijing Municipality (JQ22019)
  • National Natural Science Foundation of China (82270009, 82172278, 82070005)
  • National Key Research and Development Program of China (2023YFC0872500)
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Pulmonary Hypertension Research and Treatments
  • Health Sciences › Medicine › Rheumatology › Systemic Sclerosis and Related Diseases
Keywords
TREM2, pulmonary fibrosis, lung inflammation, sphingolipid metabolism, sphingomyelin synthesis, lung macrophages, macrophage heterogeneity, monocyte-derived macrophages, chemokines, MCP-1, bleomycin-induced fibrosis, soluble TREM2, lipidomics, chemotaxis
MeSH terms
Animals, Bleomycin, Humans, Male, Membrane Glycoproteins, Mice, Inbred C57BL, Pneumonia, Pulmonary Fibrosis, Receptors, Immunologic, Sphingolipids, Macrophages, Alveolar, Mice, Knockout, Lipid Metabolism, Mice

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CoChat. (2026). Citation check: Blockade of TREM2 ameliorates pulmonary inflammation and fibrosis by modulating sphingolipid metabolism. https://app.cochat.ai/papers/10.1016/j.trsl.2024.10.002
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Gu, X., Kang, H., Cao, S., Tong, Z., & Song, N. (2025). Blockade of TREM2 ameliorates pulmonary inflammation and fibrosis by modulating sphingolipid metabolism. Translational Research. https://doi.org/10.1016/j.trsl.2024.10.002