TREM-1 deficiency attenuates RIPK3/MLKL-associated epithelial injury in Klebsiella pneumoniae-induced acute lung injury.

Authors

Wei Zhang, Song Meng, Jiali Huang, Enfang Xiao, Yang Bai, Li Zhao, Kaifei Wang

Published in

Frontiers in cell and developmental biology. Volume 14. Pages 1974113. Epub Oct 13, 2026.

Abstract

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.
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.
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.
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.

PMID:
42947807
Bibliographic data and abstract were imported from PubMed on 28 Oct 2026.

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