TREM-1 deficiency attenuates RIPK3/MLKL-associated epithelial injury in Klebsiella pneumoniae-induced acute lung injury
6 affiliations
- 1Department of Respiratory and Critical Care Medicine, First Medical Center, Chinese PLA General Hospital, Beijing, China
- 2Department of Respiratory and Critical Care Medicine, Mudanjiang Frist People’s Hospital, Mudanjiang, Heilongjiang, China
- 3The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning, China
- 4Department of Emergency, First Medical Center, Chinese PLA General Hospital, Beijing, China
- 5Department of Cardiology,First Medical Center, Chinese PLA General Hospital, Beijing, China
- 6Department of Respiratory and Critical Care Medicine, Peking University Shougang Hospital, Beijing, China
Abstract
Background: Klebsiella pneumoniae (KP)-induced acute lung injury involves excessive myeloid inflammation, epithelial barrier disruption, and inflammatory cell death. Triggering receptor expressed on myeloid cells 1 (TREM-1) amplifies innate immune responses, whereas receptor-interacting protein kinase 3 (RIPK3)/mixed lineage kinase domain-like protein (MLKL) signaling contributes to membrane injury. Their relationship during bacterial lung infection remains incompletely understood.
Methods: KP-induced acute lung injury was established in wild-type and Trem1-deficient mice, and GSK872 was administered prophylactically to inhibit RIPK3. Lung histopathology, inflammatory mediators, and RIPK3/MLKL activation were assessed. Two human lung single-cell RNA-sequencing datasets containing non-fibrotic and fibrotic tissues were analyzed as cross-disease, hypothesis-generating reference cohorts. In vitro, conditioned medium from KP-stimulated THP-1-derived macrophage-like cells was applied to BEAS-2B epithelial cells; macrophage TREM-1 was blocked with LP17, and epithelial RIPK3 was silenced using siRNA.
Results: KP challenge increased pulmonary TREM-1 abundance and was accompanied by histopathological injury and altered inflammatory mediator concentrations. Trem1 deficiency reduced these responses together with RIPK3 and MLKL phosphorylation. Prophylactic GSK872 administration produced changes in the same direction. In the human fibrosis reference cohorts, TREM1 was concentrated in inflammatory myeloid populations, and ligand-receptor inference identified candidate macrophage-to-epithelial communication pathways. In vitro, KP increased TREM-1 and inflammatory mediator release from macrophage-like cells. Their conditioned medium induced epithelial membrane injury, RIPK3/MLKL phosphorylation, and loss of E-cadherin and ZO-1; these effects were attenuated by macrophage LP17 pretreatment or epithelial RIPK3 knockdown.
Conclusion: Trem1 deficiency attenuated KP-induced acute lung injury and was associated with reduced pulmonary inflammation and RIPK3/MLKL activation. The combined findings support a functional relationship between macrophage TREM-1-dependent inflammatory activation and epithelial RIPK3/MLKL-associated injury, rather than a fully established linear signaling axis. This intercellular injury network warrants further mechanistic and post-infection therapeutic evaluation.
Related
- Heat stress enhances Klebsiella pneumoniae-induced cellular injury and impairs milk fat synthesis in bovine mammary epithelial cells
- Clinical factors associated with carbapenem resistance and in-hospital mortality in Klebsiella pneumoniae bloodstream infection: a 7-year retrospective cohort study
- Galectin-1 deficiency attenuates imiquimod-induced psoriasiform skin inflammation and is associated with reduced macrophage recruitment
- Follistatin-like 1 Promotes Neutrophil-mediated Host Defense against Klebsiella pneumoniae
- Genomic Insights into Multi-Drug-Resistant, Klebsiella pneumoniae Isolated from an Infertile Woman: A Comprehensive Analysis of Antibiotic Resistance and Virulence Factors
BibTeX
@article{zhang2026trem1,
title = {{TREM-1 deficiency attenuates RIPK3/MLKL-associated epithelial injury in Klebsiella pneumoniae-induced acute lung injury}},
author = {Wei Zhang and Song Meng and Jiali Huang and Enfang Xiao and Yang Bai and Li Zhao and Kaifei Wang},
journal = {Frontiers in Cell and Developmental Biology},
year = {2026},
month = oct,
doi = {10.3389/fcell.2026.1974113},
url = {https://doi.org/10.3389/fcell.2026.1974113},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - TREM-1 deficiency attenuates RIPK3/MLKL-associated epithelial injury in Klebsiella pneumoniae-induced acute lung injury
AU - Wei Zhang
AU - Song Meng
AU - Jiali Huang
AU - Enfang Xiao
AU - Yang Bai
AU - Li Zhao
AU - Kaifei Wang
PY - 2026
DA - 2026/10/13
JO - Frontiers in Cell and Developmental Biology
DO - 10.3389/fcell.2026.1974113
UR - https://doi.org/10.3389/fcell.2026.1974113
AB - Background: Klebsiella pneumoniae (KP)-induced acute lung injury involves excessive myeloid inflammation, epithelial barrier disruption, and inflammatory cell death. Triggering receptor expressed on myeloid cells 1 (TREM-1) amplifies innate immune responses, whereas receptor-interacting protein kinase 3 (RIPK3)/mixed lineage kinase domain-like protein (MLKL) signaling contributes to membrane injury. Their relationship during bacterial lung infection remains incompletely understood. Methods: KP-induced acute lung injury was established in wild-type and Trem1-deficient mice, and GSK872 was administered prophylactically to inhibit RIPK3. Lung histopathology, inflammatory mediators, and RIPK3/MLKL activation were assessed. Two human lung single-cell RNA-sequencing datasets containing non-fibrotic and fibrotic tissues were analyzed as cross-disease, hypothesis-generating reference cohorts. In vitro, conditioned medium from KP-stimulated THP-1-derived macrophage-like cells was applied to BEAS-2B epithelial cells; macrophage TREM-1 was blocked with LP17, and epithelial RIPK3 was silenced using siRNA. Results: KP challenge increased pulmonary TREM-1 abundance and was accompanied by histopathological injury and altered inflammatory mediator concentrations. Trem1 deficiency reduced these responses together with RIPK3 and MLKL phosphorylation. Prophylactic GSK872 administration produced changes in the same direction. In the human fibrosis reference cohorts, TREM1 was concentrated in inflammatory myeloid populations, and ligand-receptor inference identified candidate macrophage-to-epithelial communication pathways. In vitro, KP increased TREM-1 and inflammatory mediator release from macrophage-like cells. Their conditioned medium induced epithelial membrane injury, RIPK3/MLKL phosphorylation, and loss of E-cadherin and ZO-1; these effects were attenuated by macrophage LP17 pretreatment or epithelial RIPK3 knockdown. Conclusion: Trem1 deficiency attenuated KP-induced acute lung injury and was associated with reduced pulmonary inflammation and RIPK3/MLKL activation. The combined findings support a functional relationship between macrophage TREM-1-dependent inflammatory activation and epithelial RIPK3/MLKL-associated injury, rather than a fully established linear signaling axis. This intercellular injury network warrants further mechanistic and post-infection therapeutic evaluation.
SN - 2296-634X
ER -