Mammalian Target of Rapamycin in Inflammatory Skin Conditions

Abstract

The conserved serine/threonine kinase mammalian target of rapamycin (mTOR) is a major regulator of survival growth, proliferation and motility, in response to mitogens, energy and nutrient levels. Dysregulation of mTOR pathway has been observed in various inflammatory or neoplastic human diseases. To assess the potential involvement of mTOR in some of the most common inflammatory skin diseases, and its interaction with other inflammatory mediators, we investigated mTOR expression in psoriasis, allergic contact dermatitis (ACD) and atopic dermatitis (AD). mTOR gene expression was assessed in the following conditions: i) skin biopsies from 15 patients affected by psoriasis, 5 patients with ACD, 5 patients with AD and 3 patients with EGFR-inhibitor-induced skin rash; ii) in immortalized keratinocytes HaCaT, primary human keratinocytes (KCs) and full thickness skin organ cultures, incubated with tumor necrosis factor (TNF)-a, interleukin (IL) 17A or their combination; iii) in HaCaT cells stimulated with ultraviolet (UV)B; iv) in skin biopsies from 5 psoriatic patients before and after 16 weeks of anti-TNF -a therapy; mTOR expression was also evaluated through immunohistochemistry in lesional and non-lesional skin samples from 5 psoriatic patients. Moreover, mTOR major up-stream and down-stream regulator gene expression was assessed in skin biopsies from 15 patients affected by psoriasis, 5 patients with ACD, 5 patients with AD and 3 patients with EGFR-inhibitor-induced skin rash. All analyzed skin diseases showed an increase of mTOR gene expression whereas mTOR up-stream negative regulators were reduced or not enhanced in all of them. mTOR was strongly expressed in all epidermal layers of lesional and non-lesional psoriatic skin. Conversely, pro-inflammatory conditions, in vitro, were not able to increase mTOR levels, except for UVB. Similarly, anti-TNF-a therapy was not able to reduce mTOR gene expression in patients with psoriasis. Our study provides evidence that mTOR is involved in cutaneous inflammatory process, but through a signalling not directly dependent from Thl-Thl7 pathway.The mammalian target of rapamycin (mTOR) is an ubiquitous and constitutively expressed serine/ threonine kinase, identified and cloned almost 20 years ago (1-2). This kinase has many different functional roles, exerting its effects through two distinct signalling complexes known as mTOR complex (mTORC) 1 and mTORC2. Particularly, the activation of mTORCI leads to increased cell growth and proliferation, meanwhile mTORC2 is involved in the regulation of cell polarity and in the

Negative regulation of the FOXO3a transcription factor by mTORC2 induces a pro-survival response following exposure to ultraviolet-B irradiation

“…In the skin, reports show increased levels of both mTORC1 and mTORC2 activity during progression from normal keratinocytes to pre-cancerous actinic keratosis, and finally to NMSC [63]. Dysregulation of the mTOR pathway in keratinocytes is not limited to NMSC but has also been observed in multiple inflammatory skin diseases, including acne, psoriasis and dermatitis [64, 65]. In addition, it has been shown that mTORC1 inhibition with topical rapamycin blocks dermal inflammation that is associated with the hyperproliferative response to tumor promotion [66].…”

Crosstalk between skin inflammation and adipose tissue-derived products: pathogenic evidence linking psoriasis to increased adiposity

“…In the context of adaptive immunity, leptin is involved in T cell generation, maturation and survival [93]. It mediates Th1 phenotype differentiation by increasing IFN-γ, TNF-α and IL-2 production, while it inhibits rapamycin-induced Treg cells, by increasing activation of mammalian target of rapamycin (mTOR), which is up-regulated in psoriatic skin as well as in others inflammatory skin conditions (allergic contact dermatitis and atopic dermatitis) [90,94]. Moreover, leptin promotes CD4+ cell differentiation into Th17 cells and augments IL-17A production [95].…”

Mechanistic target of rapamycin complex 1 is involved in psoriasis and regulated by anti‐TNF‐α treatment

“…[3] When active, mTORC1 phosphorylates and activates its downstreameffectorribosomalproteinS6kinase1(S6K1)involved incellproliferation. [1] Someinflammatoryskindiseasesarecharac-terizedbyelevatedlevelsofmTOR, [4][5][6] andtherearefewreports indicating an increase of mTOR and S6K1 in psoriasis too. [4,7] Up tonow,thelinkbetweenmTORC1andTNFα in psoriasis has not beenyetelucidatedeventhoughitiswellknownthatTNFα is an upstream signal of mTORC1 and also one of main protagonists of the disease.…”