Abstract:Exosomes are naturally occurring small membrane-enclosed nanovesicles that modulate the immune system and mediate communication between cells and the transport of cellular components. Although the field of exosome research in cancer progression is expanding, there are very few studies on the role of exosomes in immune-mediated inflammatory diseases. This study shows, for the first time, the presence of circulating exosomes in patients with psoriasis, in particular in those with moderate-to-severe psoriasis, th… Show more
“…By illustrating plasma IL6 kinetics and its relationship with IL17A, we determined the availability of IL6 as PD marker to illustrate the IL17A signaling status [29][30][31], by which the successful antagonization of IL17A resulted in distinct IL6 suppression 0.5 h after IMQ application. The kinetical character of IL17A/IL6 activation in this model is summarized in Fig.…”
Background
Interleukin-17A (IL17A) is a proinflammatory cytokine critically involved in autoimmune diseases, and monoclonal antibodies of IL17A have been approved for clinical treatment of psoriasis. However, a usable psoriatic animal model has been always required for preclinical evaluation of IL17A antagonists. Imiquimod (IMQ)-induced psoriasis model is widely used in fundamental research, but it’s not able to accurately show anti-psoriatic effect of IL17A antagonists with conventional modelling condition.
Results
On female C57BL/6 mice, with optimization on the usage of IMQ, positive control reagent and anti-mIL17A antibody, a 7-day model with proper testing window, acceptable disease severity as well as high repeatability was developed, and the efficacy of IL17A antagonist can be objectively evaluated by several qualitative and quantitative indices. Meanwhile, we validated the detailed involvement of IL17A signaling in disease progression, confirmed that the expression levels of IL17A and its related cytokines were induced by IMQ application, and its downstream cytokines can be inhibited by IL17A antagonist treatment. In further study, we revealed that IL17A was transient induced by IMQ and directly caused downstream signaling activation. This finding on the kinetical change of IL17A signaling will manifest the pharmacokinetics-pharmacodynamics investigation of IL17A antagonists.
Conclusions
Our work presents the application of a convenient psoriatic animal model in the research and development of IL17A antagonists, meanwhile providing extra evidence for understanding IL17A’s role in the progression of IMQ-induced psoriasis model, which manifest the research and development of IL17A antagonists.
“…By illustrating plasma IL6 kinetics and its relationship with IL17A, we determined the availability of IL6 as PD marker to illustrate the IL17A signaling status [29][30][31], by which the successful antagonization of IL17A resulted in distinct IL6 suppression 0.5 h after IMQ application. The kinetical character of IL17A/IL6 activation in this model is summarized in Fig.…”
Background
Interleukin-17A (IL17A) is a proinflammatory cytokine critically involved in autoimmune diseases, and monoclonal antibodies of IL17A have been approved for clinical treatment of psoriasis. However, a usable psoriatic animal model has been always required for preclinical evaluation of IL17A antagonists. Imiquimod (IMQ)-induced psoriasis model is widely used in fundamental research, but it’s not able to accurately show anti-psoriatic effect of IL17A antagonists with conventional modelling condition.
Results
On female C57BL/6 mice, with optimization on the usage of IMQ, positive control reagent and anti-mIL17A antibody, a 7-day model with proper testing window, acceptable disease severity as well as high repeatability was developed, and the efficacy of IL17A antagonist can be objectively evaluated by several qualitative and quantitative indices. Meanwhile, we validated the detailed involvement of IL17A signaling in disease progression, confirmed that the expression levels of IL17A and its related cytokines were induced by IMQ application, and its downstream cytokines can be inhibited by IL17A antagonist treatment. In further study, we revealed that IL17A was transient induced by IMQ and directly caused downstream signaling activation. This finding on the kinetical change of IL17A signaling will manifest the pharmacokinetics-pharmacodynamics investigation of IL17A antagonists.
Conclusions
Our work presents the application of a convenient psoriatic animal model in the research and development of IL17A antagonists, meanwhile providing extra evidence for understanding IL17A’s role in the progression of IMQ-induced psoriasis model, which manifest the research and development of IL17A antagonists.
“…To the best of our knowledge, there have been no reports on the immunomodulatory effects of IL-17-expressing sEVs from γδ T cells in cancer. Of note though, IL-17-containing sEVs were found at much higher levels in patients with moderate to severe psoriasis compared to those with mild psoriasis ( 187 ), suggesting that IL-17-containing sEVs may correlate with disease progression. Unfortunately, the cell type of origin for these IL-17-containing sEVs is unknown.…”
Section: Immunosuppressive Effects Of Immune Cell-derived Sevs In Canmentioning
Extracellular vesicles (EVs) are a heterogenous group of membrane-surrounded structures. Besides serving as a harbor for the unwanted material exocytosed by cells, EVs play a critical role in conveying intact protein, genetic, and lipid contents that are important for intercellular communication. EVs, broadly comprised of microvesicles and exosomes, are released to the extracellular environment from nearly all cells either via shedding from the plasma membrane or by originating from the endosomal system. Exosomes are 40–150 nm, endosome-derived small EVs (sEVs) that are released by cells into the extracellular environment. This review focuses on the biological properties of immune cell-derived sEVs, including composition and cellular targeting and mechanisms by which these immune cell-derived sEVs influence tumor immunity either by suppressing or promoting tumor growth, are discussed. The final section of this review discusses how the biological properties of immune cell-derived sEVs can be manipulated to improve their immunogenicity.
“…Emerging evidence highlights the immunologic role of IL-17, a pro-inflammatory cytokine secreted from T helper 17 cells (T h 17 cells) [13]. Levels of IL-17α in EVs of dermal dendritic cells (DCs) were correlated with the severity of the disease symptoms [14]. Additionally, microRNAs (miRNAs) contained within psoriatic keratinocyte EVs induce the polarization of T cells to a more inflamed state.…”
Section: Role Of Extracellular Vesicles In Skin Diseasesmentioning
Extracellular vesicles (EVs), naturally secreted by cells, act as mediators for communication between cells. They are transported to the recipient cells along with cargoes such as nucleic acids, proteins, and lipids that reflect the changes occurring within the parent cells. Thus, EVs have been recognized as potential theranostic agents for diagnosis, treatment, and prognosis. In particular, the evidence accumulated to date suggests an important role of EVs in the initiation and progression of skin aging and various skin diseases, including psoriasis, systemic lupus erythematosus, vitiligo, and chronic wounds. This review highlights recent research that investigates the role of EVs and their potential as biomarkers and therapeutic agents for skin diseases and aging.
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