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Therapeutic TNF Inhibitors Exhibit Differential Levels of Efficacy in Accelerating Cutaneous Wound Healing

ABSTRACT: Adalimumab, but neither etanercept nor certolizumab-pegol, has been reported to induce a wound healing profile in the circulation of patients with hidradenitis suppurativa (HS), a chronic inflammatory skin disease. However, the role of tumor necrosis factor alpha (TNF) inhibitors in cutaneous wound healing in vivo is still unclear. To examine and compare the efficacy of various TNF inhibitors in cutaneous wound healing in vivo, a human TNF knock-in Leprdb/db mouse model was established to model the impaired cutaneous wound healing as seen in HS. The vehicle group exhibited severe impairments in cutaneous wound healing. In contrast, adalimumab significantly accelerated healing, confirmed by both histologic assessment and a unique healing transcriptional profile. Moreover, adalimumab and infliximab showed similar levels of efficacy, but golimumab was less effective, along with etanercept and certolizumab-pegol. In line with histologic assessments, proteomics analyses from healing wounds exposed to various TNF inhibitors revealed distinct and differential wound healing signatures that may underlie the differential efficacy of these inhibitors in accelerating cutaneous wound healing. Taken together, these data revealed that TNF inhibitors exhibited differential levels of efficacy in accelerating cutaneous wound healing in the impaired wound healing model in vivo likely through distinct mechanisms of action related to the structure of the biologic or its ability to bind TNF.

ORGANISM(S): Mus musculus

PROVIDER: GSE242837 | GEO | 2023/09/11

REPOSITORIES: GEO

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Project description:The success of TNF inhibitors for treatment of psoriasis and other inflammatory diseases was previously attributed to blockade of innate immunity. In a clinical trial using etanercept TNF blocking agent to treat psoriasis vulgaris, we used affymetrix gene arrays to analyze broad gene profiles in lesional skin at multiple timepoints during drug treatment (baseline, and weeks 1, 2, 4 and 12) compared to non-lesional skin. This analysis created a temporal model of TNF-dependent gene regulation that informs molecular mechanisms of TNF-mediated inflammation. We identified four gene clusters that were differentially down-modulated during etanercept treatment: the cluster down-regulated most rapidly contained mostly dendritic cell activation genes. Culturing human keratinocytes with TNF, IFNg and IL-17 generated a list of keratinocyte genes regulated by each cytokine. The IL-17 pathway genes were strongly down-modulated early, whereas IFNg pathway genes were not down-modulated until final disease resolution at week 12. Finally, we show that TNF blockade rapidly inhibits IL-12/IL-23 p40 subunit expression, and that p40 neutralization inhibits psoriatic dermal emigre-mediated Th17 polarization. We hypothesize that etanercept inhibits myeloid dendritic cell production of IL-23, a Th17 survival cytokine, resulting in rapid downregulation of IL-17 pathway genes. This data links effects of TNF blockade on the innate immune system with the adaptive immune system. Experiment Overall Design: In this study 15 patients with moderate-to-severe psoriasis were given 50mg of etanercept (Amgen) biweekly for 12 weeks. And analyzed using gene array on mRNA extracted from tissue collected at each biopsy time point (non-lesional Time: 0; lesional Time: 0, weeks 1, 2, 4, and 12). Patients were stratified as 'responders' or 'non-responders' based on whether or not they achieved histologic disease resolution by week 12 of etanercept treatment (decreased epidermal thickening, normalization of proliferation marker Ki67, and loss of differentiation marker K16).

Project description:Extracellular vesicles (EVs) are on the edge of innovation aimed at regenerative and therapeutic applications, including wound healing, by containing therapeutic agents originating from secreting cells. Moreover, silver nanoparticles (AgNPs) play a role in wound healing because they have antiseptic activities. Therefore, in this study, we used sequencing technology to investigate the mRNA profile in UCMSC-derived exosomes (EXs). We also attempted to determine the role of the transcriptome, particularly in cutaneous wound healing, using bioinformatics analysis. Additionally, we investigated the efficacy of utilising a combination of UCMSC-derived EXs and AgNPs on burned animal models. Results showed that a large number of protein-coding genes (4578 genes) have been detected in UCMSC-derived EXs, among which 2004 genes are upregulated in exosomes while 2574 genes are downregulated compared to secreting cells. Interestingly, many genes enriched in exosomes were associated with the biology of the wound healing process. Gene ontology (GO) term and Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway analysis indicated the upregulated exosomal genes belonging to GO terms and KEGG pathways related to signaling pathways such as DNA replication, ribosome, cell cycle, and pyrimidine metabolism. Further investigations that aimed to test exosomes and AgNPs in wound healing stimulation confirmed the faster healing capacity belongs to all exosomes, AgNPs, and a combination of EXs and AgNPs in the early healing process. The exosomes also expressed their capacity to enhance the dermal fibroblast proliferation. Our findings indicated the selective sorting of mRNAs into EXs, the potential of EXs, and the combination of EXs with AgNPs in cutaneous wound healing. Extracellular vesicles (EVs) are on the edge of innovation aimed at regenerative and therapeutic applications, including wound healing, by containing therapeutic agents originating from secreting cells. Moreover, silver nanoparticles (AgNPs) play a role in wound healing because they have antiseptic activities. Therefore, in this study, we used sequencing technology to investigate the mRNA profile in UCMSC-derived exosomes (EXs). We also attempted to determine the role of the transcriptome, particularly in cutaneous wound healing, using bioinformatics analysis. Additionally, we investigated the efficacy of utilising a combination of UCMSC-derived EXs and AgNPs on burned animal models. Results showed that a large number of protein-coding genes (4578 genes) have been detected in UCMSC-derived EXs, among which 2004 genes are upregulated in exosomes while 2574 genes are downregulated compared to secreting cells. Interestingly, many genes enriched in exosomes were associated with the biology of the wound healing process. Gene ontology (GO) term and Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway analysis indicated the upregulated exosomal genes belonging to GO terms and KEGG pathways related to signaling pathways such as DNA replication, ribosome, cell cycle, and pyrimidine metabolism. Further investigations that aimed to test exosomes and AgNPs in wound healing stimulation confirmed the faster healing capacity belongs to all exosomes, AgNPs, and a combination of EXs and AgNPs in the early healing process. The exosomes also expressed their capacity to enhance the dermal fibroblast proliferation. Our findings indicated the selective sorting of mRNAs into EXs, the potential of EXs, and the combination of EXs with AgNPs in cutaneous wound healing. Extracellular vesicles (EVs) are on the edge of innovation aimed at regenerative and therapeutic applications, including wound healing, by containing therapeutic agents originating from secreting cells. Moreover, silver nanoparticles (AgNPs) play a role in wound healing because they have antiseptic activities. Therefore, in this study, we used sequencing technology to investigate the mRNA profile in UCMSC-derived exosomes (EXs). We also attempted to determine the role of the transcriptome, particularly in cutaneous wound healing, using bioinformatics analysis. Additionally, we investigated the efficacy of utilising a combination of UCMSC-derived EXs and AgNPs on burned animal models. Results showed that a large number of protein-coding genes (4578 genes) have been detected in UCMSC-derived EXs, among which 2004 genes are upregulated in exosomes while 2574 genes are downregulated compared to secreting cells. Interestingly, many genes enriched in exosomes were associated with the biology of the wound healing process. Gene ontology (GO) term and Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway analysis indicated the upregulated exosomal genes belonging to GO terms and KEGG pathways related to signaling pathways such as DNA replication, ribosome, cell cycle, and pyrimidine metabolism. Further investigations that aimed to test exosomes and AgNPs in wound healing stimulation confirmed the faster healing capacity belongs to all exosomes, AgNPs, and a combination of EXs and AgNPs in the early healing process. The exosomes also expressed their capacity to enhance the dermal fibroblast proliferation. Our findings indicated the selective sorting of mRNAs into EXs, the potential of EXs, and the combination of EXs with AgNPs in cutaneous wound healing.

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Therapeutic TNF Inhibitors Exhibit Differential Levels of Efficacy in Accelerating Cutaneous Wound Healing

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