Comparative Analysis of the Biosimilar and Innovative G-CSF Modulated Pathways on Umbilical Cord Blood–Derived Mononuclear Cells

Ávila-Portillo, Luz Mábel; Aristizábal, Fabio; Pérdomo, Sandra; Riveros, Angela; Ospino, Benjamín; Avila, J. P.; Butti, Matías; Abba, Martı́n C.

doi:10.1177/1177932220913307

Cited by 2 publications

(4 citation statements)

References 29 publications

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“…In addition, we performed bulk RNA sequencing (RNA-seq) of neutrophils from Plcg2 S707Y/+ mice, which revealed a gene expression signature that closely resembles that of cells treated with G-CSF (Extended Data Fig. 2h ) 21 . Taken together, autoinflammation in APLAID was not solely dependent on IL-6, inflammasome or TNF; however, G-CSF production was clearly dysregulated.…”

Section: Resultsmentioning

confidence: 99%

“…Macrophage samples and neutrophil samples were analyzed separately. Enrichment of gene sets 21 was tested using the roast method 60 and illustrated using barcode plots drawn by limma’s barcodeplot function.…”

Section: Methodsmentioning

confidence: 99%

“…Heatmap colours represent mean cytokine values. h) Enrichment of gene sets 21 are shown as barcode plots drawn by Limma’s barcode plot function. Data are derived from 2 independent experiments with 4 (n = 5) and 6-week-old (n = 6) PLCγ2 S707Y/+ mice and age-, number- and sex-matched littermate controls.…”

Section: Extended Datamentioning

confidence: 99%

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G-CSF drives autoinflammation in APLAID

et al. 2023

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Missense mutations in PLCG2 can cause autoinflammation with phospholipase C gamma 2-associated antibody deficiency and immune dysregulation (APLAID). Here, we generated a mouse model carrying an APLAID mutation (p.Ser707Tyr) and found that inflammatory infiltrates in the skin and lungs were only partially ameliorated by removing inflammasome function via the deletion of caspase-1. Also, deleting interleukin-6 or tumor necrosis factor did not fully prevent APLAID mutant mice from autoinflammation. Overall, these findings are in accordance with the poor response individuals with APLAID have to treatments that block interleukin-1, JAK1/2 or tumor necrosis factor. Cytokine analysis revealed increased granulocyte colony-stimulating factor (G-CSF) levels as the most distinct feature in mice and individuals with APLAID. Remarkably, treatment with a G-CSF antibody completely reversed established disease in APLAID mice. Furthermore, excessive myelopoiesis was normalized and lymphocyte numbers rebounded. APLAID mice were also fully rescued by bone marrow transplantation from healthy donors, associated with reduced G-CSF production, predominantly from non-hematopoietic cells. In summary, we identify APLAID as a G-CSF-driven autoinflammatory disease, for which targeted therapy is feasible.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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G-CSF drives autoinflammation in APLAID

et al. 2023

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“…Several studies address the potential modulatory effects of G-CSF and IL-6 on MSCs in vitro. Stimulation of MSCs by G-CSF was shown to modulate various pathways, including the metabolism of hyaluronan and migratory capacity, specifically through reduced CD44 expression [ 67 ]. MSC treatment with IL-6 resulted in increased production of pro-inflammatory cytokines [ 68 ].…”

Section: Discussionmentioning

confidence: 99%

Equilibrium among Inflammatory Factors Determines Human MSC-Mediated Immunosuppressive Effect

Suzdaltseva

Goryunov

Silina

et al. 2022

Cells

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Mesenchymal stem cells (MSCs) are thought to be a promising therapeutic agent due to their multiple paracrine and immunomodulatory properties, providing protection from chronic inflammation and promoting tissue repair. MSCs can regulate the balance of pro-inflammatory and anti-inflammatory factors in inflamed tissues, creating a microenvironment necessary for successful healing; however, their interactions with immune cells are still poorly studied. We examined the temporal and spatial changes in gene regulation and the paracrine milieu accompanying the MSC-mediated immunosuppression effect in mixed cultures with activated peripheral blood mononuclear cells (PBMCs). Our data reveal that the peak of suppression of PBMC proliferation was achieved within 48 h following co-culture with MSCs and subsequently did not undergo a significant change. This effect was accompanied by an increase in COX-2 expression and an induction of IDO synthesis in MSCs. At this point, the expression of IL-1, IL-6, IL-8, IFN-γ, MCP-1, and G-CSF was upregulated in co-cultured cells. On the contrary, we observed a decrease in the concentrations of IL-10, IL-13, IL-5, and MIP-1b in co-culture supernatants compared to intact cultures of activated PBMCs. The regulation of IDO, IL-1, IL-6, and G-CSF production was accomplished with the involvement of direct cell–cell contact between MSCs and PBMCs. These findings provide new insights into the use of potential precondition inducers or their combinations to obtain functionally qualified MSCs for more effective treatment of inflammatory diseases.

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Comparative Analysis of the Biosimilar and Innovative G-CSF Modulated Pathways on Umbilical Cord Blood–Derived Mononuclear Cells

Cited by 2 publications

References 29 publications

G-CSF drives autoinflammation in APLAID

G-CSF drives autoinflammation in APLAID

Equilibrium among Inflammatory Factors Determines Human MSC-Mediated Immunosuppressive Effect

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