Gene expression profiling of skin and blood in hidradenitis suppurativa

Blok, J. L.; Li, K.; Brodmerkel, Carrie; Jonkman, Marcel F.; Hórvath, Barbara

doi:10.1111/bjd.14371

Cited by 55 publications

(74 citation statements)

References 10 publications

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“…Similar to our findings, the pathways affected were mostly related to inflammation, including cell adhesion, diapedesis and extravasation, as well as immune cell signalling and communication pathways. After relaxing the stringent filtering criteria used in our study we could also identify a dysregulation of atherosclerosis signalling as reported by Blok et al ., indicating an association between HS inflammation and metabolic syndrome . Hotz et al .…”

Section: Discussionsupporting

confidence: 71%

“…A limited number of studies has focused on the analysis of molecular profile changes at the gene and/or protein levels. Blok et al . performed mRNA profiling of LS vs. NLS and further investigated these changes in whole blood of HS patients and control subjects.…”

Section: Discussionmentioning

confidence: 99%

“…Coates et al . have compared the HS microarray data set of Block et al ., with a transcriptional signature of biopsy‐induced wounds of the human skin and the oral mucosa published by Iglesias‐Bartolome et al . and suggested that the pathogenesis of HS may be driven by changes in antimicrobial peptide expression and altered sweat gland function and may share a similar pathology with chronic wounds.…”

Section: Discussionmentioning

confidence: 99%

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Alterations in innate immunity and epithelial cell differentiation are the molecular pillars of hidradenitis suppurativa

Zouboulis

Costa

Makrantonaki

et al. 2020

Acad Dermatol Venereol

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Background The large unmet need of hidradenitis suppurativa/acne inversa (HS) therapy requires the elucidation of disease‐driving mechanisms and tissue targeting. Objective Robust characterization of the underlying HS mechanisms and detection of the involved skin compartments. Methods Hidradenitis suppurativa/acne inversa molecular taxonomy and key signalling pathways were studied by whole transcriptome profiling. Dysregulated genes were detected by comparing lesional and non‐lesional skin obtained from female HS patients and matched healthy controls using the Agilent array platform. The differential gene expression was confirmed by quantitative real‐time PCR and targeted protein characterization via immunohistochemistry in another set of female patients. HS‐involved skin compartments were also recognized by immunohistochemistry. Results Alterations to key regulatory pathways involving glucocorticoid receptor, atherosclerosis, HIF1α and IL17A signalling as well as inhibition of matrix metalloproteases were detected. From a functional standpoint, cellular assembly, maintenance and movement, haematological system development and function, immune cell trafficking and antimicrobial response were key processes probably being affected in HS. Sixteen genes were found to characterize HS from a molecular standpoint (DEFB4, MMP1, GJB2, PI3, KRT16, MMP9, SERPINB4, SERPINB3, SPRR3, S100A8, S100A9, S100A12, S100A7A (15), KRT6A, TCN1, TMPRSS11D). Among the proteins strongly expressed in HS, calgranulin‐A, calgranulin‐B and serpin‐B4 were detected in the hair root sheath, koebnerisin and connexin‐32 in stratum granulosum, transcobalamin‐1 in stratum spinosum/hair root sheath, small prolin‐rich protein‐3 in apocrine sweat gland ducts/sebaceous glands‐ducts and matrix metallopeptidase‐9 in resident monocytes. Conclusion Our findings highlight a panel of immune‐related drivers in HS, which influence innate immunity and cell differentiation in follicular and epidermal keratinocytes as well as skin glands.

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Section: Discussionsupporting

confidence: 71%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Alterations in innate immunity and epithelial cell differentiation are the molecular pillars of hidradenitis suppurativa

Zouboulis

Costa

Makrantonaki

et al. 2020

Acad Dermatol Venereol

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“…[12,13] Statistically significant elevations in plasma C3a (P = .006), C5a (P = .004) and [12,13] Statistically significant elevations in plasma C3a (P = .006), C5a (P = .004) and…”

Section: Dys Reg Ul Ati On Of Complement Is a Sso Ciated With D Is mentioning

confidence: 99%

Integrating complement into the molecular pathogenesis of Hidradenitis Suppurativa

Grand

Navrazhina

Frew

2019

Experimental Dermatology

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Complement inhibition has been identified as a potential therapeutic target for multiple inflammatory disorders including Hidradenitis Suppurativa (HS). It is currently unclear how complement integrates into our current model of molecular pathogenesis in HS and whether it represents a central component of pathogenesis, or a neutrophil-associated bystander. Levels of C5a in serum and tissue correlate with disease activity and degree of neutrophilic infiltrates in HS. C5a has been associated with Th17 immune axis activation in psoriasis, rheumatoid arthritis and Crohn's disease with strong similarities to TH17 activation in HS. Porphyromonas species (which are identified in the HS microbiome) are able to cleave inactive C5 into C5a implicating the cutaneous microbiome as an activator of complement. C3a and C5a are associated with activation of the NLRP3 inflammasome, implicated in the inflammatory drive in HS. Complement receptors are present upon dendritic cells, monocytes, fibroblasts and adipocytes, which may broaden the potential contribution of complement to multiple aspects of HS pathogenesis. Dysregulation of complement receptor pathways has been documented in obesity, insulin resistance and polycystic ovarian syndrome leading to the possibility that complement may explain the epidemiological associations between these conditions and HS. The therapeutic potential of complement inhibitors in HS may be related to the therapeutic target (complement receptor or complement subunit) and the presence of alternate receptors (such as C5aR2) or ligands (including C3a, PAMPs and DAMPs). Integrating complement into the known pathogenesis of HS may aid in explaining the contradictory results between Phase 2 studies of C5a antagonists. It also allows for the identification of existing knowledge gaps to target further clinical investigation and research.

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“…Hidradenitis suppurativa (HS) is a chronic, inflammatory skin disease affecting the pilosebaceous units in the axilla, groin and buttocks. Current hypotheses propose that HS results from hair follicle instability and occlusion, followed by hair follicle rupture, and aberrant immune response, which creates a pathogenic cycle of tissue damage and inflammation …”

Section: Introductionmentioning

confidence: 99%

E‐cadherin and p120ctn protein expression are lost in hidradenitis suppurativa lesions

Nelson

Cong

Gettle

et al. 2019

Experimental Dermatology

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Hidradenitis suppurativa (HS) is a chronic, inflammatory skin disease affecting the pilosebaceous units in the axilla, groin and buttocks. While the pathogenesis of HS is not clear, mechanical stress exacerbates HS. In this study, we aimed to determine whether intracellular adhesive junctions may be aberrant in HS patient skin. Strikingly, we observed loss of E‐cadherin and p120ctn protein expression, two key adherens junction proteins, in ~85% of HS severe skin lesions. Moreover, loss of protein expression was apparent in non‐lesional skin from HS patients and the degree of loss positively correlated with HS Hurley Stage of disease. E‐cadherin expression was unaltered in other inflammatory skin conditions including chronic wound epithelium, atopic dermatitis, and acne vulgaris compared with healthy skin suggesting that its loss may be uniquely relevant to HS pathogenesis. A complete loss of α‐catenin, β‐catenin and ZO‐1 was not observed; however, some cytoplasmic staining of the catenins was noted in HS epithelium. We also demonstrated diminished desmosome size in HS lesional skin. Overall, our data suggested that loss of adherens junction proteins and diminished desmosome size in HS skin contributes to the skin's inability to withstand mechanical stress and provides rationale as to why mechanical stress exacerbates HS symptoms.

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Gene expression profiling of skin and blood in hidradenitis suppurativa

Cited by 55 publications

References 10 publications

Alterations in innate immunity and epithelial cell differentiation are the molecular pillars of hidradenitis suppurativa

Alterations in innate immunity and epithelial cell differentiation are the molecular pillars of hidradenitis suppurativa

Integrating complement into the molecular pathogenesis of Hidradenitis Suppurativa

E‐cadherin and p120ctn protein expression are lost in hidradenitis suppurativa lesions

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