Transcriptomic and lipidomic profiling of eicosanoid/docosanoid signalling in affected and non‐affected skin of human atopic dermatitis patients

Abstract

Lipoxygenases (LOX) and cyclooxygenase (COX) are the main enzymes for PUFA metabolism to highly bio‐active prostaglandins, leukotrienes, thromboxanes, lipoxins, resolvins and protectins. LOX and COX pathways are important for the regulation of pro‐inflammatory or pro‐resolving metabolite synthesis and metabolism for various inflammatory diseases such as atopic dermatitis (AD). In this study, we determined PUFAs and PUFA metabolites in serum as well as affected and non‐affected skin samples from AD patients and the dermal expression of various enzymes, binding proteins and receptors involved in these LOX and COX pathways. Decreased EPA and DHA levels in serum and reduced EPA level in affected and non‐affected skin were found; in addition, n3/n6‐PUFA ratios were lower in affected and non‐affected skin and serum. Mono‐hydroxylated PUFA metabolites of AA, EPA, DHA and the sum of AA, EPA and DHA metabolites were increased in affected and non‐affected skin. COX1 and ALOX12B expression, COX and 12/15‐LOX metabolites as well as various lipids, which are known to induce itch (12‐HETE, LTB4, TXB2, PGE2 and PGF2) and the ratio of pro‐inflammatory vs pro‐resolving lipid mediators in non‐affected and affected skin as well as in the serum of AD patients were increased, while n3/n6‐PUFAs and metabolite ratios were lower in non‐affected and affected AD skin. Expression of COX1 and COX‐metabolites was even higher in non‐affected AD skin. To conclude, 12/15‐LOX and COX pathways were mainly upregulated, while n3/n6‐PUFA and metabolite ratios were lower in AD patients skin. All these parameters are a hallmark of a pro‐inflammatory and non‐resolving environment in affected and partly in non‐affected skin of AD patients.

PPAR‐γ signalling as a key mediator of human hair follicle physiology and pathology

“…Since all PPARs are widely expressed in human skin and its appendages, there is increasing interest in their role in maintaining cutaneous homeostasis and in dermatological disorders . PPAR‐mediated signalling has attracted special interest in psoriasis, atopic dermatitis, acne, skin ageing, scleroderma, melasma, lipodystrophy and skin cancer . In the context of this Focus Theme Issue , this development encourages one to also take a closer look at why and how exactly PPARs are of special interest in a translational hair research context, with a strict focus on their best‐investigated isoform, PPAR‐γ.…”

“…While all PPARs have been assigned important functions in human skin physiology, and although PPAR‐β/δ is the most abundant isotype, most dermatological research has focused on PPAR‐γ, arguably the best‐investigated of all PPARs, for which synthetic agonists are available and in clinical use, targeting e.g. inflammation, cell proliferation and/or apoptosis . PPAR‐γ reportedly can be found throughout human skin but is particularly prominently expressed by adipocytes, suprabasal epidermal keratinocytes and sebocytes .…”

“…inflammation, cell proliferation and/or apoptosis. [8,9,36] PPAR-γ reportedly can be found throughout human skin but is particularly prominently expressed by adipocytes, suprabasal epidermal keratinocytes and sebocytes. [39,[50][51][52] PPAR-γ-mediated signalling stimulates, for example, lipid synthesis in the epidermis, induces keratinocyte differentiation, enhances barrier homeostasis and promotes sebocyte differentiation in the sebaceous gland (SG).…”

Xenobiotic Receptors and Their Mates in Atopic Dermatitis

“…However, there is agreement on a shift from very long chain to shorter-chain fatty acids (FAs) in ceramides of the stratum corneum in AD skin, regardless of skin lesions and FLG null mutations, thus causing further disruption of the lamellar bilayer organization [27,29,30,31,32]. Moreover, the amounts of ω3 and ω6 polyunsaturated FAs (PUFAs) and of their downstream metabolites are altered in AD skin [25,33,34]. These results are in line with transcriptomic analyses showing dysregulated expression of lipid-related genes in AD skin [35,36,37].…”

“…PPARA mRNA levels are reduced in lesional AD skin when compared to healthy and nonlesional skin [34,246], similar to PPARG [34]. Cellular abnormalities in lesional AD skin include production of alarmins, also referred as to DAMPs (TSLP, IL-33, HMGB1 and IL-α), by damaged KCs.…”