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Dynamics of Stage-specific Immune Remodeling by Neutrophils and Macrophages in Acute Lung Injury

ABSTRACT: Acute lung injury (ALI) is driven by dysregulated alveolar immune responses. While granulocytes and macrophages are critical effectors, their coordinated molecular reprogramming remains poorly defined. However, the evolving crosstalk and stage-specific functional transitions of these populations have been overlooked. Here, we performed single-cell RNA sequencing (scRNA-seq) of bronchoalveolar lavage fluid from intermediate and late-stage ALI patients to map immune microenvironment remodeling. We observed pronounced granulocyte expansion coupled with macrophage depletion. Granulocytes exhibit distinct trajectories from acute migratory states toward pro-inflammatory, metabolically reprogrammed subsets, dominated by TNF and MAPK signaling. Simultaneously, macrophages transition toward inflammatory M1-like phenotypes, characterized by distinct metabolic reprogramming and reduced oxidative phosphorylation. Furthermore, we identify a granulocyte-centric inflammatory network mediated through TNF, IFN, and RESISTIN pathways, establishing pathogenic feedback loops. Collectively, this study elucidates the transcriptional and metabolic reprogramming driving ALI progression, providing a framework for stage-adapted therapeutic interventions to restore pulmonary homeostasis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE315604 | GEO | 2026/01/05

REPOSITORIES: GEO

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Project description:Chronic myelomonocytic leukemia (CMML) is a clonal malignancy characterized by overlapping myeloid dysplasia and proliferation with persisting monocytosis. Characteristic repartitioning of classical monocytes is now a supporting diagnostic criterion (WHO5), though its mechanistic basis remains unknown. While monocytes are the cardinal malignant cell type in CMML, as a stem cell neoplasm the disease clone comprises most lineages and differentiation stages including granulocytes. To investigate the pathogenic contribution of granulocytes in CMML maintenance and progression, we have performed molecular and functional characterization of CMML granulocytes. Compared with healthy age-matched controls, CMML granulocytes exhibited defective maturation with reduced granularity and phagocytic capacity. Transcriptome analysis revealed activation of pathways linked to proliferation, Myc activity and inflammation. Notably, RETN, which encodes inflammatory mediator Resistin, was upregulated 100-fold in CMML granulocytes; but not differentially expressed in CMML PBMNCs, sorted monocytes, or stem and progenitor cells compared to their healthy counterparts. Accordingly, Resistin protein levels were 10-fold higher in plasma from CMML patients and higher plasma Resistin levels correlate with poor overall survival. Remarkably, exposure of healthy monocytes to exogenous recombinant Resistin induced classical monocyte repartition, recapitulating the pattern seen in CMML, and inhibited macrophage differentiation. Transcriptome analysis of Resistin treated monocytes revealed that Resistin induces gene signatures related to immune suppression and myeloid-derived suppressor cell phenotype. We found SEMA4A to be a downstream target of Resisin and is overexpressed in CMML monocytes. Consistent with known roles for SEMA4A, CMML patients displayed higher percentage of T-regs and elevated Th2/Th1 ratio compared with healthy controls, apparently corresponding with associated Resistin levels. Furthermore, we demonstrated that Resistin directly induces the T-reg expansion and skews the Th2/Th1 ratio by binding to monocytes. In conclusion, we showed that immature granulocytes in CMML produce high levels of Resistin, which contributes to classical monocytosis phenotype and immune suppression.

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Dynamics of Stage-specific Immune Remodeling by Neutrophils and Macrophages in Acute Lung Injury

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