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

Abstract

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.

Aetiology and pathogenesis of hidradenitis suppurativa

“…Inflammation eventually leads to clinically visible dermal nodules and abscesses. The formation of pus-draining epithelialized sinus tracts and fistulas may be supported by the continued formation of pus, known to occur in the massive presence of neutrophilic granulocytes and bacteria, the seeding of follicular stem cells into the disintegrated tissue, 67 the abundance of MMPs, 64 and the loosening of cell-cell adhesive junctions in the epidermis 69 (Figure 3). Chronification of inflammation leads to destruction of skin architecture, recurring development of abscesses, wounding, and subsequent fibrotic scarring.…”

Yin and Yang: A disrupted skin microbiome and an aberrant host immune response in hidradenitis suppurativa

“…189,190 HS has been associated with atopic dermatitis and eczema, as well as IBD, where barrier integrity and microbiome dysbiosis are also present. [96][97][98]191,192 In addition to these associations, multiple studies have illustrated that the HS skin structure is altered, with abnormalities noted in the expression and location of cytokeratins, integrins, desmosomes and adherens junctions 11,13,[193][194][195][196] Notably,…”

“…p120ctn and E-cadherin are completely absent throughout the epidermis in severe lesions, suggesting an adherens junction defect in HS skin. 196 Lastly, autoantibodies against filaggrin are present in HS serum. 169 Whether these autoantibodies against filaggrin can disrupt skin structure is currently unclear.…”

Candida albicans and candidalysin in inflammatory disorders and cancer

“…74 In addition to structural defences, a healthy epithelium provides front-line induction of innate immune responses through release of alarmins, AMPs and immune cell chemokines, all of which are additionally compromised upon loss of barrier integrity. Notably, periodontal, 75-77 gut [78][79][80] and skin [81][82][83] disorders are commonly associated with the loss of E-cadherin, resulting in enhanced barrier permeability and inflammatory pathology, with restoration of E-cadherin showing improvement in disease outcomes. 84 Candida albicans infection has also been shown to diminish E-cadherin expression in both in vivo and in vitro infection models, [85][86][87] with candidalysin highlighted as a direct contributor to epithelial damage, loss of barrier integrity and subsequent translocation of C. albicans across the intestinal epithelia.…”

“…In addition to structural defences, a healthy epithelium provides front‐line induction of innate immune responses through release of alarmins, AMPs and immune cell chemokines, all of which are additionally compromised upon loss of barrier integrity. Notably, periodontal, 75–77 gut 78–80 and skin 81–83 disorders are commonly associated with the loss of E‐cadherin, resulting in enhanced barrier permeability and inflammatory pathology, with restoration of E‐cadherin showing improvement in disease outcomes 84 …”