Inhibition of RelA expression via RNA interference induces immune tolerance in a rat keratoplasty model

Yang, Jize; Feng, Songfu; Yi, Guoguo; Wu, Wei; Yi, Ruiwen; Lu, Xiaoyan; Xu, Wanfu; Qiu, Haijiang

doi:10.1016/j.molimm.2016.03.014

Cited by 16 publications

(5 citation statements)

References 33 publications

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“…Importantly, lentiviral generation of tolerogenic DCs has shown promising therapeutic effects not only in animal models of autoimmune disorders but also in allograft rejection. In this regard, a recent study shows how the knockdown of RelA, a positive regulator of NF- κ B activation, attenuates the corneal allograft rejection in an animal model of allogeneic corneal transplant [33]. In the present work, we show that, by mean of lentiviral transduction, the permanent STAT3 activity or the constitutive NF- κ B repression induces the generation of tolerogenic DCs with therapeutic activity in a mouse model of RA.…”

Section: Resultssupporting

confidence: 60%

“…Interestingly, a group of studies performed in animal models has shown lentiviral transduction as a potent tool to insert immunosuppressive genes or to knock down proinflammatory features in DCs. In this way, the adoptive transfer of tolerogenic DCs generated by lentiviral transduction has been shown to exert a potent antigen-specific immunosuppressive therapy not only ameliorating autoimmune disorders but also attenuating allograft rejection and systemic inflammation associated with septic shock [30–33]. According to the potent and stable phenotype acquired by DCs upon lentiviral transduction and considering the important role of STAT3 and NF- κ B as regulators of DC behaviour, in this study, we aimed to test the therapeutic potential of the permanent NF- κ B inhibition and constitutive STAT3 activation given by lentiviral transduction to DCs, each alone or both together, in a mouse model of CIA.…”

Section: Introductionmentioning

confidence: 99%

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STAT3 Activation in Combination with NF-KappaB Inhibition Induces Tolerogenic Dendritic Cells with High Therapeutic Potential to Attenuate Collagen-Induced Arthritis

Prado

Ugalde

González

et al. 2019

Journal of Immunology Research

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Dendritic cells (DCs) have the ability to induce tolerance or inflammation in response to self-antigens, which makes them fundamental players in autoimmunity. In this regard, immunogenic DCs produce IL-12 and IL-23 favouring the acquisition of Th1 and Th17 inflammatory phenotypes, respectively, by autoreactive CD4+ T-cells, thus promoting autoimmunity. Conversely, tolerogenic DCs produce IL-10 and TGF-β, inducing the generation of CD4+ T-cells with suppressive activity (Treg), which promote tolerance to self-constituents. Previous studies have shown that STAT3 signalling in DCs attenuates the production of proinflammatory cytokines, whilst NF-κB activation promotes it. In this study, we aimed to generate DCs displaying strong and constitutive tolerogenic profile to be used as immunotherapy in autoimmunity. To this end, we transduced bone marrow-derived DCs with lentiviral particles codifying for a constitutively active version of STAT3 (constitutively active STAT3 (STAT3ca)) or with a constitutive repressor of NF-κB (IκBα superrepressor (IκBαSR)), and their therapeutic potential was evaluated in a mouse model of arthritis induced by collagen (CIA). Our results show that STAT3ca transduction favoured the production of the anti-inflammatory mediator IL-10, whereas IκBαSR transduction attenuated the expression of the proinflammatory cytokine IL-23 in DCs. Moreover, both STAT3ca-transduced and IκBαSR-transduced DCs separately exerted a mild but significant therapeutic effect reducing the severity of CIA development. Furthermore, when DCs were transduced with both STAT3ca and IκBαSR together, they reduced CIA manifestation significantly stronger than when transduced with only STAT3ca or IκBαSR separately. These results show STAT3 and NF-κB as two important and complementary regulators of the tolerogenic behaviour of DCs, which should be considered as molecular targets in the design of DC-based suppressive immunotherapies for the treatment of autoimmune disorders.

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Section: Resultssupporting

confidence: 60%

Section: Introductionmentioning

confidence: 99%

STAT3 Activation in Combination with NF-KappaB Inhibition Induces Tolerogenic Dendritic Cells with High Therapeutic Potential to Attenuate Collagen-Induced Arthritis

Prado

Ugalde

González

et al. 2019

Journal of Immunology Research

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“…11 In a series of clinical investigation, the safety of the application of tolerogenic DCs has been proved for autoimmune disorders administration. 12 The adoptive transfer of tolerogenic DCs exerts antigen-specific immunosuppressive therapeutic effects that attenuate allograft rejection 13 with no affection of the salutary immune response. DCs can be derived from DC-committed precursors (pre-DCs) in the bone marrow (BM), which contain several subsets based on their phenotypic and functional difference.…”

Section: Introductionmentioning

confidence: 99%

Mir‐27a‐3p attenuates bronchiolitis obliterans in vivo via the regulation of dendritic cells’ maturation and the suppression of myofibroblasts’ differentiation

Dong

Wang

Tong

et al. 2020

Clinical & Translational Med

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Bronchiolitis obliterans (BO), is a chronic rejection phenotype characterized by chronic small airway fibrous obliteration, hinders the patients who suffer from lung transplanting for surviving longer. Cell‐based therapies using dendritic cells (DCs) and T regulatory cells (Tregs) have been developed to regulate allograft rejection, and to induce and maintain immune tolerance. In the present study, the effects of mir‐27a‐3p on regulating DCs as well as resulting effects on BO attenuation have been investigated. According to our reporter assays, the potential targets of mir‐27a‐3p were Smad2, sprouty2, and Smad4, respectively. Furthermore, sprouty2 inhibition by mir‐27‐3p indirectly activated extracellular regulated protein kinases (ERK) and increased IL‐10 production in DCs. This led to a positive feedback loop that maintained the immature state of DCs via IL‐10/JAK/STAT3 pathway, and caused an increase in Foxp3+CD4+ T cells amount as well as TGF‐β level. Furthermore, mir‐27a‐3p regulated TGF‐β function, inhibited TGF‐β/Smad pathway, and suppressed myofibroblast differentiation through influencing the function of Smad2 and Smad4. In short, the study indicated the effect of mir‐27a‐3p on suppressing DC maturation, which implicated the potential clinical application in treating postlung transplant BO.

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“…The generation of mouse BMDCs was carried out in accordance with the method outlined in a previously established protocol ( 24 ). In short, after the C57BL/6 mice were killed by cervical dislocation, their femurs were removed from the ultra-clean experimental table, sterilized, and repeatedly rinsed with sterilized PBS.…”

Section: Methodsmentioning

confidence: 99%

NECA alleviates inflammatory responses in diabetic retinopathy through dendritic cell toll-like receptor signaling pathway

Li,

Chen,

Wang

et al. 2024

Front. Immunol.

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IntroductionThis study examined the impact of 5’-(N- ethylcarboxamido)adenosine (NECA) in the peripheral blood of healthy individuals, those with diabetes mellitus, diabetic retinopathy (DR), and C57BL/6 mice, both in vivo and in vitro.MethodsEnzyme-linked immunosorbent assay (ELISA) and flow cytometry (FCM) were used to evaluate the effects of NECA on dendritic cells (DCs) and mouse bone marrow-derived dendritic cells (BMDCs) and the effects of NECA-treated DCs on Treg and Th17 cells. The effect of NECA on the Toll-like receptor (TLR) pathway in DCs was evaluated using polymerase chain reaction (PCR) and western blotting (WB).ResultsFCM and ELISA showed that NECA inhibited the expression of surface markers of DCs and BMDCs, increased anti-inflammatory cytokines and decreased proinflammatory cytokines. PCR and WB showed that NCEA decreased mRNA transcription and protein expression in the TLR-4-MyD88-NF-kβ pathway in DCs and BMDCs. The DR severity in streptozocin (STZ) induced diabetic mice was alleviated. NECA-treated DCs and BMDCs were co-cultivated with CD4+T cells, resulting in modulation of Treg and Th17 differentiation, along with cytokine secretion alterations.ConclusionNECA could impair DCs’ ability to present antigens and mitigate the inflammatory response, thereby alleviating the severity of DR.

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Inhibition of RelA expression via RNA interference induces immune tolerance in a rat keratoplasty model

Cited by 16 publications

References 33 publications

STAT3 Activation in Combination with NF-KappaB Inhibition Induces Tolerogenic Dendritic Cells with High Therapeutic Potential to Attenuate Collagen-Induced Arthritis

STAT3 Activation in Combination with NF-KappaB Inhibition Induces Tolerogenic Dendritic Cells with High Therapeutic Potential to Attenuate Collagen-Induced Arthritis

Mir‐27a‐3p attenuates bronchiolitis obliterans in vivo via the regulation of dendritic cells’ maturation and the suppression of myofibroblasts’ differentiation

NECA alleviates inflammatory responses in diabetic retinopathy through dendritic cell toll-like receptor signaling pathway

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