Integrated single-cell and spatial transcriptomic atlas of multi-etiology acute lung injury reveals etiology-dependent neutrophil fate decisions and a prognostic neutrophil-monocyte/macrophage interaction signature.
Summary
This study integrated single-cell RNA sequencing from 180,031 murine lung cells across seven acute lung injury models with spatial transcriptomics. It identified 13 neutrophil subtypes, etiology-dependent fate trajectories, a 26-gene neutrophil-monocyte/macrophage interaction index associated with sepsis mortality, and THBS1-CD36 signaling as a mechanistically actionable target.
Key Findings
- Single-cell profiles from 180,031 murine lung cells across seven acute lung injury models were integrated with spatial transcriptomics.
- Thirteen neutrophil subtypes and four broad neutrophil macro-states were identified, with sepsis and bacterial infection retaining neutrophils near an immature state.
- A 26-gene neutrophil-monocyte/macrophage interaction index showed prognostic value for sepsis mortality.
- Blocking THBS1-CD36 with CD36 peptide P(93-110) reduced inflammatory activation, promoted reparative macrophage polarization, and lowered circulating neutrophils in vivo.
Clinical Implications
The 26-gene interaction index may support future molecular risk stratification in sepsis-associated lung injury, while THBS1-CD36 blockade could become a therapeutic strategy. Both require validation in human tissues, prospective cohorts, and appropriately powered interventional trials before clinical use.
Why It Matters
The work challenges the assumption that neutrophils have a uniform role across acute lung injury etiologies. By linking spatially resolved cellular states to a prognostic signature and in vivo pathway blockade, it provides a mechanistic framework for precision treatment of infection-related lung injury and sepsis.
Limitations
- The principal experimental evidence is derived from murine acute lung injury models and may not reproduce human sepsis biology.
- The prognostic 26-gene signature requires external validation in independent human cohorts.
- The therapeutic experiments do not establish clinical dosing, safety, or efficacy in patients.
Future Directions
Future studies should validate the neutrophil states and interaction index in human sepsis-associated acute lung injury, develop clinically feasible assays, determine whether THBS1-CD36 blockade improves organ outcomes, and define treatment windows and safety parameters.
Study Information
- Study Type
- Cohort
- Research Domain
- Pathophysiology
- Evidence Level
- III - A mechanistic preclinical multi-model study with integrated omics and in vivo validation; translational evidence remains preclinical.
- Study Design
- OTHER