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S100A8/A9 contributes to inflammatory exacerbations in neutrophils and monocytes from PAMI syndrome

ABSTRACT: Proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1)-associated myeloid-related proteinemia inflammatory (PAMI) syndrome is a monogenic autoinflammatory disease characterized by progressive arthritis with neutrophilic infiltration, cytopenia, and high serum S100A8/A9 and zinc. The molecular pathophysiology of PAMI caused by particular variants of the PSTPIP1 gene, such as PSTPIP1 E250K, is still unknown, and targeted therapy based on the pathogenesis has not been developed. We established an analytical model of neutrophils and monocytes/macrophages using induced pluripotent stem cells harboring the PAMI variant and another PSTPIP1 E250Q variant observed in PSTPIP1-related disorders with milder phenotypes. Using the model cells, we demonstrated increased production of reactive oxygen species, inflammatory cytokines, S100A8/9, increased cell death in the E250K neutrophils, and increased production of cytokines and abnormal phenotype of E250K monocytes/macrophages. With these model cells, we delved into the molecular basis of the hyperinflammation and pronounced S100A8/A9 production. Our data revealed that S100A8/A9 was at the center of hyperinflammation in PAMI syndrome and its deletion can reverse functional and molecular abnormalities in the phagocytes.

ORGANISM(S): Homo sapiens

PROVIDER: GSE270695 | GEO | 2026/06/25

REPOSITORIES: GEO

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Project description:Background: Non-healing wounds cause profound suffering of patients and a huge economic burden on society. Current research attempts to refine MSC-based therapies for this type of difficult-to-treat wounds. We earlier reported that injection of S100A8/A9 primed MSCs into the wound edge in mice accelerates wound healing compared to non-primed MSCs. We here describe a protective response of differentially expressed isoforms of genes, proteins and their potential role in the reported beneficial effects of S100A8/A9 primed MSCs on tissue repair. Methods: Adipose‐derived MSCs were characterized for specific cell surface markers using flow cytometry and assessed for their ability to differentiate into different lineages. To further investigate the mechanisms underlying the beneficial effects of S100A8/A9 primed MSCs, we employed a multi‐omics strategy that combined transcriptome, secretome, and proteome analyses. Global translational activity and a potential metabolic shift were examined using fluorescent labeling alongside seahorse‐based metabolic assays. Additionally, in silico analysis was conducted to assess the presence of the DRACH motif in mRNAs encoding these proteins, thereby evaluating their potential for cap-independent, m6A‐mediated translation. Results: Enhanced protein translation was observed in MSCs primed with S100A8/A9. Priming significantly increased the levels of the cap-independent translation initiation factor EIF3I, while reducing the cap-dependent factor EIF4A1, suggesting a shift in the mode of translation. In addition, the secretome of S100A8/A9-primed MSCs exhibited upregulation of cystatin C, a tissue protective protease inhibitor, and angiopoietin-1, an inducer of angiogenesis. Furthermore, various collagens, which serve as MSC niche-protecting proteins, were expressed at higher levels in the S100A8/A9 primed MSCs. Notably, the mRNAs corresponding to these factors contained DRACH motifs. Conclusion: We uncovered a protective response in S100A8/A9 primed MSCs that alters translation processes and increases the secretion of protective proteins, whose functions warrant further exploration. In the long term, S100A8/A9 priming holds promise for developing more effective MSC‐based therapies to enhance wound healing.

Project description:To shed light on the early processes of immune response to peripheral nerve injury, we first used genome-wide transcriptional profiling and bioinformatics (Ingenuity, NextBio) pathway analyses of the proximal (P; regenerating) and distal (D; degenerating) nerve stumps at day 1 in the sciatic nerve axotomy model in rats. We identified a number of specific immunomodulatory genes and pathways that were regulated shortly post-injury in both the P and D segments, including all members of the interleukin (IL), chemokine, tumor necrosis factor (TNF), matrix metalloproteinase (MMP), toll-like receptor (TLR), tissue inhibitor of metalloproteinase (TIMP), ion channel and myosin families. Immunomodulatory calcium-binding S100A8 and S100A9 were the top up-regulated genes in both the D and P segments. In cultured Schwann cells stimulated with the purified S100A8/A9 heterodimer we recorded a high level of similarity of the activated genes and pathways with that of the injured nerve, especially in the activation of the chemokine and cytokine gene networks that support agranulocyte and granulocyte chemotaxis, adhesion, transmigration and rolling signaling pathways. We also confirmed activation of multiple cell death related gene networks supporting TNFR1, natural killer cell receptor and death receptor apoptosis signaling in the D stump, and the gluconeogenesis/glycolysis and cytoskeletal motility signaling in the P stump, corroborated by activation of ERK, PI3K and JNK kinase pathways. As compared to the D segment, multiple additional pathways were more efficiently upregulated in the P stump, including the IL-6 and -17, MMP-9, calcium, activated agranulocyte, leukocyte rolling and glutathione-mediated detoxification signaling pathways. These data suggest that shortly after nerve injury, upregulation of S100A8/A9 is responsible for the expression and release of chemokines and cytokines by Schwann cells, necessary to generate the initial chemotactic gradient and guide the hematogenous immune cells into the injury site. Gene expression profiling of total RNAs extracted from injured and non-injured rat sciatic nerves, and primary rat Schwann cells stimulated with S100A8/A9 proteins

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S100A8/A9 contributes to inflammatory exacerbations in neutrophils and monocytes from PAMI syndrome

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