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
Using 180,031 murine lung cells across seven infectious, sterile, and extrapulmonary injury models, the authors resolved 13 neutrophil subtypes and four macro-states with etiology-specific transcriptional programs. They identified a prognostic 26-gene neutrophil–monocyte/macrophage interaction index and showed that blocking THBS1-CD36 attenuated macrophage NF-κB-MAPK-NLRP3 activation, promoted reparative polarization, and reduced circulating neutrophils in vivo.
Key Findings
- Single-cell profiles from 180,031 murine lung cells across seven acute lung injury models identified etiology-specific neutrophil programs.
- High-resolution analysis defined 13 neutrophil subtypes organized into four macro-states and revealed an etiology-dependent bifurcation from immature bone marrow-like cells toward interferon/inflammasome or NF-κB inflammatory states.
- A 26-gene neutrophil–monocyte/macrophage interaction index predicted sepsis mortality, and THBS1-CD36 blockade reduced inflammatory activation and circulating neutrophils in vivo.
Clinical Implications
The 26-gene interaction index could support biological stratification and prognosis research in sepsis-associated acute lung injury. THBS1-CD36 blockade is not yet clinically established, but the findings justify translational validation in human samples and preclinical safety and efficacy studies.
Why It Matters
This study moves beyond viewing neutrophils as a uniform pathogenic population by defining etiology-dependent cell states and a mechanistically testable neutrophil–macrophage signaling axis. The THBS1-CD36 pathway provides a concrete therapeutic hypothesis for infection- and endotoxin-driven acute lung injury.
Limitations
- The principal atlas and intervention experiments were conducted in murine models, so human cellular states and therapeutic effects remain to be confirmed.
- The prognostic interaction index requires independent validation in well-characterized human acute lung injury and sepsis cohorts.
Future Directions
Future work should validate the THBS1-CD36 axis in human bronchoalveolar and blood samples, define which etiologic subgroups are most likely to benefit, and evaluate pharmacokinetics, safety, and efficacy of pathway inhibition in translational models.
Study Information
- Study Type
- Cohort
- Research Domain
- Pathophysiology
- Evidence Level
- IV - A preclinical, multi-model mechanistic study with transcriptomic discovery and in vivo intervention, without direct clinical efficacy evidence.
- Study Design
- OTHER