STAT4 expression and activation is increased during mitosisin vitroandin vivoin skin- and mucosa-derived cell types: implications in neoplastic and inflammatory skin diseases

The aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor expressed in all skin cell types, plays a key role in physiological and pathological processes. Several studies have shown that this receptor is involved in the prevention of inflammatory skin diseases, e.g., psoriasis, atopic dermatitis, representing a potential therapeutic target. We tested the safety profile and the biological activity of NPD-0614-13 and NPD-0614-24, two new synthetic AhR ligands structurally related to the natural agonist FICZ, known to be effective in psoriasis. NPD-0614-13 and NPD-0614-24 did not alter per se the physiological functions of the different skin cell populations involved in the pathogenesis of inflammatory skin diseases. In human primary keratinocytes stimulated with tumor necrosis factor-α or lipopolysaccharide the compounds were able to counteract the altered proliferation and to dampen inflammatory signaling by reducing the activation of p38MAPK, c-Jun, NF-kBp65, and the release of cytokines. Furthermore, the molecules were tested for their beneficial effects in human epidermal and full-thickness reconstituted skin models of psoriasis. NPD-0614-13 and NPD-0614-24 recovered the psoriasis skin phenotype exerting pro-differentiating activity and reducing the expression of pro-inflammatory cytokines and antimicrobial peptides. These data provide a rationale for considering NPD-0614-13 and NPD-0614-24 in the management of psoriasis.

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Crosstalk between keratinocytes and immune cells in inflammatory skin diseases

Exploration of Immunology ◽

10.37349/ei.2021.00028 ◽

2021 ◽

pp. 418-431

Author(s):

Xinhui Ni ◽

Yuping Lai

Keyword(s):

Immune Cells ◽

Skin Diseases ◽

Inflammatory Responses ◽

Cell Types ◽

Cell Type ◽

Physical Barrier ◽

Inflammatory Skin Diseases ◽

Major Cell Type ◽

Inflammatory Skin ◽

Different Cell Types

Cutaneous homeostasis is maintained by dynamic cellular communications between different cell types in the skin through interactions with various mediators, including cytokines, chemokines and antimicrobial peptides/proteins (AMPs). Keratinocytes, as the major cell type of the epidermis, not only form a passive physical barrier, but also actively participate in the pathogenesis of many, if not all, inflammatory skin diseases. Keratinocytes highly interact with immune cells to shape, amplify or regulate inflammatory responses, thus triggering and/or sustaining these inflammatory skin diseases. In this review, crosstalk between keratinocytes and immune cells is summarized, and its contributions to two major inflammatory skin disorders including psoriasis and atopic dermatitis are highlighted.

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Stem Cells-Derived Extracellular Vesicles: Potential Therapeutics for Wound Healing in Chronic Inflammatory Skin Diseases

International Journal of Molecular Sciences ◽

10.3390/ijms22063130 ◽

2021 ◽

Vol 22 (6) ◽

pp. 3130

Author(s):

Enzo Manchon ◽

Nell Hirt ◽

Jean-David Bouaziz ◽

Nabila Jabrane-Ferrat ◽

Reem Al-Daccak

Keyword(s):

Stem Cells ◽

Extracellular Vesicles ◽

Skin Diseases ◽

Therapeutic Potential ◽

Cell Types ◽

Parental Cell ◽

Inflammatory Skin Diseases ◽

Beneficial Effects ◽

Cell Source ◽

Inflammatory Skin

Endosome-derived small extracellular vesicles (EVs), often referred to as exosomes, are produced by almost all, if not all, cell types, and are critical for intercellular communication. They are composed of a lipid bilayer associated with membrane proteins and contain a payload of lipids, proteins and regulatory RNAs that depends on the parental cell physiological condition. By transferring their “cargo”, exosomes can modulate the phenotype of neighboring and distant cells. Stem cells (SC) were widely studied for therapeutic applications regarding their regenerative/reparative potential as well as their immunomodulatory properties. Whether from autologous or allogeneic source, SC beneficial effects in terms of repair and regeneration are largely attributed to their paracrine signaling notably through secreted EVs. Subsequently, SC-derived EVs have been investigated for the treatment of various diseases, including inflammatory skin disorders, and are today fast-track cell-free tools for regenerative/reparative strategies. Yet, their clinical application is still facing considerable challenges, including production and isolation procedures, and optimal cell source. Within the emerging concept of “allogeneic-driven benefit” for SC-based therapies, the use of EVs from allogeneic sources becomes the pragmatic choice although a universal allogeneic cell source is still needed. As a unique temporary organ that ensures the mutual coexistence of two allogeneic organisms, mother and fetus, the human placenta offers a persuasive allogeneic stem cell source for development of therapeutic EVs. Advancing cell-free therapeutics nurtures great hope and provides new perspectives for the development of safe and effective treatment in regenerative/reparative medicine and beyond. We will outline the current state of the art in regard of EVs, summarize their therapeutic potential in the context of skin inflammatory disorders, and discuss their translational advantages and hurdles.

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