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Transcriptionally and phenotypically dysfunctional neutrophils have a suppressive role in macrophage activation syndrome

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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Project description:Systemic juvenile idiopathic arthritis (SJIA) is a chronic childhood arthropathy with features of autoinflammation. Early inflammatory SJIA is associated with expansion and activation of neutrophils with a sepsis-like phenotype, but neutrophil phenotypes present in longstanding and clinically inactive disease (CID) are unknown. The objective of this study was to examine activated neutrophil subsets, S100 alarmin release, and gene expression signatures in children with a spectrum of SJIA disease activity. Methods: Highly-purified neutrophils were isolated using a two-step procedure of density-gradient centrifugation followed by magnetic-bead based negative selection prior to flow cytometry or cell culture to quantify S100 protein release. Whole transcriptome gene expression profiles were compared in neutrophils from children with both active SJIA and CID. Results: Patients with SJIA and active systemic features demonstrated a higher number of CD16+CD62Llo neutrophil population compared to controls. This neutrophil subset was not seen in patients with CID or patients with active arthritis not exhibiting systemic features. Using imaging flow cytometry, CD16+CD62Llo neutrophils from patients with active SJIA and features of macrophage activation syndrome (MAS) had increased nuclear hypersegmentation compared to CD16+CD62L+ neutrophils. Serum levels of S100A8/A9 and S100A12 were strongly correlated with peripheral blood neutrophil counts. Neutrophils from active SJIA patients did not show enhanced resting S100 protein release; however, regardless of disease activity, neutrophils from SJIA patients did show enhanced S100A8/A9 release upon PMA stimulation compared to control neutrophils. Furthermore, whole transcriptome analysis of highly purified neutrophils from children with active SJIA identified 214 differentially expressed genes compared to neutrophils from healthy controls. The most significantly upregulated gene pathway was Immune System Process, including AIM2, IL18RAP, and NLRC4. Interestingly, this gene set showed intermediate levels of expression in neutrophils from patients with long-standing CID yet persistent serum IL-18 elevation. Indeed, all patient samples regardless of disease activity demonstrated elevated inflammatory gene expression, including inflammasome components and S100A8. Conclusion: We identify features of neutrophil activation in SJIA patients with active disease and CID, including a proinflammatory gene expression signature, reflecting persistent innate immune activation. Taken together, these studies expand understanding of neutrophil function in chronic autoinflammatory disorders such as SJIA.

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Transcriptionally and phenotypically dysfunctional neutrophils have a suppressive role in macrophage activation syndrome

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