IL-6 and TGF-β-Secreting Adoptively-Transferred Murine Mesenchymal Stromal Cells Accelerate Healing of Psoriasis-like Skin Inflammation and Upregulate IL-17A and TGF-β

Cuesta-Gomez, Nerea; Medina-Ruiz, Laura; Graham, Gerard J.; Campbell, John

doi:10.3390/ijms241210132

Cited by 5 publications

(4 citation statements)

References 64 publications

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“…Although controversial data from in vivo studies have claimed that preconditioning MSCs with inflammatory cytokines is not essential for improvement in function in some inflammatory conditions [ 27 ], additional reports support the beneficial effect of the inflammatory stimulation of MSCs with IFN-γ [ 15 , 16 , 17 ], suggesting that the effect’s response could rely on different aspects, such as the kinds of cytokine, its concentration, and the kinds of cells. To our knowledge, no study has explicitly examined the in vitro effect of IFN-γ preconditioned hGMSCs on PBMC activation and maturation; therefore, this study first applied this strategy to evaluate and validate this effect.…”

Section: Discussionmentioning

confidence: 99%

IFN-γ-Preconditioned Human Gingival-Derived Mesenchymal Stromal Cells Inhibit Plasmacytoid Dendritic Cells via Adenosine

Ríos-Ríos,

Sosa-Luis,

Almaraz-Arreortua

et al. 2024

Biomolecules

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Plasmacytoid dendritic cells (pDCs) are vital players in antiviral immune responses because of their high levels of IFN-α secretion. However, this attribute has also implicated them as critical factors behind the immunopathogenesis of inflammatory diseases, and no currently available therapy can efficiently inhibit pDCs’ aberrant activation. Mesenchymal stromal cells (MSCs) possess stromal immunomodulatory functionality, regulating immune cell activation through several mechanisms, including the adenosinergic (CD39/CD73/adenosine) pathway. The IFN-γ preconditioning of bone marrow MSCs improves their inhibitory properties for therapy applications; however, isolating human gingival tissue-derived MSCs (hGMSCs) is more accessible. These cells have shown better immunomodulatory effects, yet the outcome of IFN-γ preconditioning and its impact on the adenosinergic pathway has not been evaluated. This study first validated the immunoregulatory properties of primary-cultured hGMSCs, and the results showed that IFN-γ preconditioning strengthens CD39/CD73 coexpression, adenosine production, and the regulatory properties of hGMSC, which were confirmed by describing for the first time their ability to reduce pDC activation and their IFN-α secretion and to increase the frequency of CD73+ pDC. In addition, when CD73′s enzymatic activity was neutralized in hGMSCs, adenosine production and the IFN-γ preconditioning effect were restrained. This evidence might be applied to design hGMSCs- and adenosine-based immunotherapeutic strategies for treating inflammatory disorders that are associated with pDC overactivation.

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Section: Discussionmentioning

confidence: 99%

IFN-γ-Preconditioned Human Gingival-Derived Mesenchymal Stromal Cells Inhibit Plasmacytoid Dendritic Cells via Adenosine

Ríos-Ríos,

Sosa-Luis,

Almaraz-Arreortua

et al. 2024

Biomolecules

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“…16 The upregulation of other cytokines, such as IL-6, IL-12, IL-22, IL-29, IL-36, IL-1 β, and tumor necrosis factorα, is also involved in the pathogenesis of psoriasis. [20][21][22][23][24][25] Among these cytokines, IL-6 is a pleiotropic cytokine involved in epithelial and immune cell angiogenesis, proliferation, and differentiation. [26][27][28][29] Owing to its excessive activation and dysregulation of receptor signaling in T cells, IL-6 is involved in the pathogenesis of psoriasis.…”

Section: Introductionmentioning

confidence: 99%

“…The upregulation of other cytokines, such as IL‐6, IL‐12, IL‐22, IL‐29, IL‐36, IL‐1 β, and tumor necrosis factor‐α, is also involved in the pathogenesis of psoriasis 20–25 . Among these cytokines, IL‐6 is a pleiotropic cytokine involved in epithelial and immune cell angiogenesis, proliferation, and differentiation 26–29 .…”

Section: Introductionmentioning

confidence: 99%

Pro‐inflammatory cytokine IL‐6 regulates LMO4 expression in psoriatic keratinocytes via AKT/STAT3 pathway

Tu,

Wei,

Xiang

et al. 2023

Immunity Inflam & Disease

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The transcription factor LIM‐only protein 4 (LMO4) is overexpressed in the psoriatic epidermis and regulates keratinocyte proliferation and differentiation. High LMO4 expression levels are induced by interleukin‐23 (IL‐23) to activate the AKT/STAT3 signaling pathway. Interleukin‐6 (IL‐6) is mainly involved in regulating T cell functions and development in patients with psoriasis. However, whether LMO4 expression is regulated by IL‐6 remains unclear. Therefore, the purpose of this study is to explore the role and molecular mechanisms of IL‐6 in regulating LMO4 expression. The interleukin‐6 (IL‐6) levels in human plasma were determined using a chemiluminescence immunoassay system. A psoriasis‐like mouse model was established using imiquimod induction. Epidermal keratinocytes (HaCaT) were cultured in defined keratinocyte‐serum‐free medium and stimulated by IL‐6 alone or with inhibitors. The proteins of interest were detected using western blot analysis, immunofluorescence, and immunohistochemistry. The 5‐ethynyl‐2′‐deoxyuridine assay was used to detect cell proliferation. The results revealed that IL‐6 levels were markedly increased in the plasma of patients with psoriasis, compared to healthy control. The high expression of LMO4 was consistent with high levels of IL‐6, p‐AKT, and p‐STAT3 in the lesions of both psoriasis patients and imiquimod‐induced psoriasis‐like mice. IL‐6 activates the AKT/STAT3 signaling pathway, followed by LMO4 high‐expression in HaCaT cells. IL‐6 induces HaCaT proliferation and differentiation via AKT/STAT3 signaling pathway activation. We think that the high expression of LMO4 in psoriatic keratinocytes requires IL‐6 to activate the AKT/STAT3 signaling pathway and leads to epidermal keratinocytes abnormal proliferation and differentiation.

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“… 14 , 15 , 16 recent research has shown that IL‐6 secreting MSC accelerates diabetes reversal through the upregulation of IL‐17A and TGF‐β in the skin. 17 Moreover, IL‐6 induces hyperproliferation and inflammation of cells, which is at least in part via the IL‐6/STAT3 (signal transducer and activator of transcription) signalling pathway, 18 a crucial signalling pathway identified in many diseases. 19 Importantly, in human keratinocytes, tripartite motif 27 (TRIM27) was found to be involved in the IL‐6/STAT3 signalling pathway by binding to PIAS3 and facilitating its ubiquitination.…”

Section: Introductionmentioning

confidence: 99%

METTL14 promotes IL‐6‐induced viability, glycolysis and inflammation in HaCaT cells via the m6A modification of TRIM27

Chen,

Xiang,

Miao

et al. 2023

J Cellular Molecular Medi

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Interleukin‐6 (IL‐6) is a cytokine generated by healthy constituents of the skin, but is also up‐regulated by a wide range of skin lesions and inflammatory conditions to trigger cytopathy of skin cells. TRIM27 was identified to contribute to the functional effects of IL‐6 on skin cells. However, the underlying mechanism was not clear. Lentivirus infection was used for gene overexpression or silencing. RT‐PCR and Western blot were used to respectively assess mRNA and protein levels. Cell viability was assessed by CCK‐8 assay. Extracellular flux analysis was used to assess the levels of oxygen consumption rate and extracellular acidification rate. Mouse back skin was treated with imiquimod to produce psoriasis‐like inflammation in vivo. Histological assessment and immunohistochemistry staining were respectively applied to analyse lesioned mouse and human skin samples. IL‐6‐induced increased viability, glycolysis and inflammation in keratinocytes was inhibited both by a chemical methylation inhibitor and by METTL14 knockdown. Further investigation found that METTL14 induces m6A methylation of TRIM27, which is recognized by a m6A reader, IGF2BP2. Elevation of TRIM27 level and activation of IL‐6/STAT3 signalling pathway were found in an in vivo psoriasis‐like inflammation model, whereas inhibition m6A methylation strongly alleviated the inflammation. Finally, METTL14, TRIM27, STAT3, p‐STAT3 and IL‐6 expressions were all found to be increased in clinical skin samples of psoriatic patients. Our results unravelled METTL14/TRIM27/IGF2BP2 signalling axis in keratinocyte cytopathy, which plays a critical role in facilitating the activation of IL‐6/STAT3 signalling pathway. Our findings should provide inspirations for the design of new therapeutics for skin inflammatory diseases including psoriasis.

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IL-6 and TGF-β-Secreting Adoptively-Transferred Murine Mesenchymal Stromal Cells Accelerate Healing of Psoriasis-like Skin Inflammation and Upregulate IL-17A and TGF-β

Cited by 5 publications

References 64 publications

IFN-γ-Preconditioned Human Gingival-Derived Mesenchymal Stromal Cells Inhibit Plasmacytoid Dendritic Cells via Adenosine

IFN-γ-Preconditioned Human Gingival-Derived Mesenchymal Stromal Cells Inhibit Plasmacytoid Dendritic Cells via Adenosine

Pro‐inflammatory cytokine IL‐6 regulates LMO4 expression in psoriatic keratinocytes via AKT/STAT3 pathway

METTL14 promotes IL‐6‐induced viability, glycolysis and inflammation in HaCaT cells via the m6A modification of TRIM27

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