Friends or Foes? Host defense (antimicrobial) peptides and proteins in human skin diseases

Autosomal recessive congenital ichthyosis (ARCI) is a group of monogenic skin disorders caused by mutations in any of at least 12 different genes, many of which are involved in the epidermal synthesis of ω‐O‐acylceramides (acylCer). AcylCer are essential precursors of the corneocyte lipid envelope crosslinked by transglutaminase‐1 (TGm‐1), or a yet unidentified enzyme, for normal skin barrier formation. We hypothesized that inactivating TGM1 mutations will lead to a compensatory overexpression of the transcripts involved in skin barrier repair, including many other ARCI‐causing genes. Using microarray, we examined the global mRNA expression profile in skin biopsies from five ARCI patients with TGM1 mutations and four healthy controls. There were a total of 599 significantly differentially expressed genes (adjusted P < 0.05), out of which 272 showed more than 1.5 log2fold‐change (FC) up‐ or down‐regulation. Functional classification of the latter group of transcripts showed enrichment of mRNA encoding proteins mainly associated with biological pathways involved in keratinocyte differentiation and immune response. Moreover, the expression of seven out of twelve ARCI‐causing genes was significantly increased (FC = 0.98‐2.05). Also, many of the genes involved in keratinocyte differentiation (cornified envelope formation) and immune response (antimicrobial peptides and proinflammatory cytokines) were upregulated. The results from the microarray analysis were also verified for selected genes at the mRNA level by qPCR and at the protein level by semi‐quantitative immunofluorescence. The upregulation of these genes might reflect a compensatory induction of acylCer biosynthesis as a part of a global barrier repair response in the patient′s epidermis.

Section: Discussionsupporting

confidence: 66%

Section: Discussionsupporting

confidence: 59%

Patients with congenital ichthyosis and TGM1 mutations overexpress other ARCI genes in the skin: Part of a barrier repair response?

Zhang

Ericsson

Weström

et al. 2018

“…More recently, low copy numbers of gene DEFB4, encoding the antimicrobial peptide (AMP) β‐defensin‐2, were shown to increase susceptibility to dermatophytosis . AMPs are involved in the skin defence against pathogens, including bacteria, virus or fungi, through direct antimicrobial activities, as well as through immunomodulatory effects and reinforcement of the epidermal barrier . The AMP β‐defensin‐2, β‐defensin‐3, RNase 7, S100A7 and cathelicidin LL‐37 inhibit in vitro the growth of various dermatophytes species, including T. rubrum , and are overexpressed in response to the presence of dermatophytes in monolayer cultures of keratinocytes, and in skin biopsies from patient with dermatophytosis …”

Section: Dermatophytosis and Dermatophytesmentioning

confidence: 99%

In vitro models of dermatophyte infection to investigate epidermal barrier alterations

Faway

Rouvroit

Poumay

2018

Dermatophytosis is a superficial fungal infection of keratinized structures caused by specific filamentous fungi named dermatophytes. In humans, the incidence of dermatophytosis is elevated and continuously increasing, rendering it a public health concern. The pathogeny of dermatophytosis remains poorly understood, partly due to the difficulties to set up a relevant model allowing the study of both the invasion of keratinized structures by fungi, and its impact on host tissue architecture and functions. Recently, the development of human cultured skin equivalents has led to some advances. This review aims to summarize current knowledge about dermatophytosis and then focuses on in vitro models to investigate the alterations of the epidermal barrier in response to fungal infection. | DERMATOPHY TOS IS AND DERMATOPHY TE SDermatophytosis is an infection of superficial keratinized epidermal layers, as well as hairs and nails, which is caused by keratinolytic filamentous fungi named dermatophytes.[1] Numerous dermatophyte species are grouped according to their ecological Genome sequencing, especially analysis of the polymorphisms inside the variable rDNA regions known as internal transcribed spacers (ITS), has provided phylogenetic criteria for improved species identification.[4] A revised classification of dermatophytes was proposed, [5][6][7] based on DNA sequences of five different loci, including ITS, on morphology and physiology in culture, and on geo-, zoo-or anthropophilic ecology (Table 1). This review is concerned with anthropophilic and zoophilic dermatophytes frequently responsible for human infections.Dermatophytosis is responsible for 3%-4% of dermatological cases and is the most common fungal infection in humans, with a prevalence estimated around 20%-25%. [8,9] In addition, its prevalence is continuously raising due to increased risk factors such as sport activities, type 2 diabetes, vascular diseases or ageing. Modern mobility further increases the dissemination of anthropophilic dermatophytes that extend in previously poorly affected geographical areas. [10,11] Among the species capable of infecting human skin,Trichophyton rubrum is the most frequently involved, being responsible for 50%-90% of dermatophytoses in humans. [9,12] The annual health expense cost of dermatophytosis is estimated to more than 500 million of US dollars.[13] | Dermatophyte infections induce various clinical picturesThe clinical signs of dermatophytosis result from both the degradation of keratinized tissues caused by fungal processes, as well as from the specific immune response of the infected host.Zoophilic species, probably less adapted to human hosts, generate more severe inflammatory responses than anthropophilic species. [6,14] Usual signs include dryness, desquamation, cracks and erythema of the skin of the feet, scalp or other body locations.Infections in hairless areas and nails, principally due to Trichophyton rubrum and Trichophyton interdigitale, are the most frequent in industrialized countries. Scalp infections, ...

“…Anti‐microbial peptides demonstrate not only bactericidal effects, but can also promote inflammatory reactions. Differential expression of AMPs was found in acne skin, among them β‐defensins, psoriasin and cathelicidin . Cathelicidin and ß‐defensins are abundantly expressed by sebocytes in response to S. aureus and C. acnes .…”

Section: Cav‐1 In Innate Immunitymentioning

confidence: 99%

Caveolin‐1 as a possible target in the treatment for acne

Kruglikov¹,

Scherer

2019

Expression of caveolin-1 (Cav-1) is an important pathophysiological factor in acne.Cav-1 strongly interacts with such well-recognized etiopathogenic factors such as hyperseborrhea, follicular hyperkeratinization and pathogenicity of Cutibacterium acnes. Cav-1 is a strong negative regulator of transforming growth factor beta (TGFβ) expression. It acts as a critical determinant of autophagy, which is significantly induced in acne lesions through C. acnes and by absorption of fatty acids. Cav-1 also demonstrates different correlations with the development of innate immunity. We propose that normalization of Cav-1 expression can serve as a target in anti-acne therapy. K E Y W O R D Sacne, autophagy, C. acnes, caveolin, follicular hyperkeratinization, hyperseborrhea, innate immunity, pathophysiology