Transcriptionally and phenotypically dysfunctional neutrophils have a suppressive role in macrophage activation syndrome
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ABSTRACT: Macrophage activation syndrome (MAS) is a life-threatening cytokine storm syndrome that complicates rheumatic diseases including systemic juvenile idiopathic arthritis (SJIA). Though neutrophil expansion and activation are key features of SJIA, MAS is associated with neutropenia. As the functional contribution of neutrophils to MAS is largely unexplored, we aimed to define neutrophil dynamics in the TLR9-induced MAS mouse model. Mice with TLR9-MAS showed a transient increase in immature neutrophils during MAS and persistent decrease of mature neutrophils through resolution, even after other MAS features were normalized. Single-cell RNA sequencing confirmed increased proportions of both interferon-stimulated gene-high and immature neutrophils during MAS. We also detected an enhanced interferon signature with upregulation of CD274 (PD-L1), suggesting immunosuppressive roles but distinct form myeloid-derived suppressor cells (MDSC). Furthermore, most of the interferon signature normalized at resolution, but prolonged suppression of IL-1 related genes persisted. Neutrophils from both acute and resolution phases of MAS showed in vitro suppression of pro-inflammatory responses upon LPS stimulation. Notably, antibody mediated neutrophil depletion exaggerated clinical, laboratory, and immunologic features of MAS. Overall, neutrophils in MAS show dynamic changes in subpopulations, including transcriptional and phenotypic dysfunction. These findings suggest that mature neutrophils may play anti-inflammatory roles in MAS and highlights an underappreciated role for neutrophil functions in the pathogenesis of cytokine storm syndromes.
ORGANISM(S): Mus musculus
PROVIDER: GSE299930 | GEO | 2025/07/15
REPOSITORIES: GEO
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