Translational implications of Th17-skewed inflammation due to genetic deficiency of a cadherin stress sensor

Abstract

Desmoglein 1 (Dsg1) is a cadherin restricted to stratified tissues of terrestrial vertebrates, which serve as essential physical and immune barriers. Dsg1 loss-of-function mutations in humans result in skin lesions, multiple allergies, and isolated patient keratinocytes exhibit increased pro-allergic cytokine expression. However, the mechanism by which genetic deficiency of Dsg1 causes chronic inflammation is unknown.To determine the systemic response to Dsg1 loss, we deleted the three tandem Dsg1 genes in mice. Whole transcriptome analysis of embryonic Dsg1 -/skin showed a delay in expression of adhesion/differentiation/keratinization genes at E17.5, a subset of which recovered or increased by E18.5.Comparing epidermal transcriptomes from Dsg1-deficient mice and humans revealed a shared IL-17skewed inflammatory signature. Although the impaired intercellular adhesion observed in Dsg1 -/mice resembles that resulting from anti-Dsg1 pemphigus foliaceus antibodies, pemphigus skin lesions exhibit a weaker IL-17 signature. Consistent with the clinical importance of these findings, treatment of two Dsg1deficient patients with an IL-12/IL-23 antagonist originally developed for psoriasis resulted in improvement of skin lesions. Thus, beyond impairing the physical barrier, loss of Dsg1 function through gene mutation results in a psoriatic-like inflammatory signature before birth and treatment with a targeted therapy markedly improved skin lesions in patients.

Pemphigus Foliaceus Autoantibodies Induce Redistribution Primarily of Extradesmosomal Desmoglein 1 in the Cell Membrane

“…In contrast, in human skin, antibodies against Dsg1 are required to induce acantholysis similar to the situation in patients, indicating that Dsg1 plays an important role for maintenance of epidermal integrity ( 15 ). This is supported by animal models where loss of Dsg1 caused lethal skin blisters in superficial epidermis, whose localization is similar to patients with PF ( 16 , 17 ). The mechanisms of antibody induced acantholysis are manifold and include direct inhibition of desmosomal cadherin binding as well as an activation of numerous signaling pathways such as p38MAPK, PKC, EGFR, PLC and ERK1/2 ( 18 – 20 ).…”

The Desmosome-Keratin Scaffold Integrates ErbB Family and Mechanical Signaling to Polarize Epidermal Structure and Function

“…On the other hand, cortical actin-associated Merlin can dampen EGFR activity in contact inhibited cells ( Chiasson-MacKenzie et al, 2015 ), and this relationship is tunable ( Kim et al, 2009 ). Further, loss of E-cadherin, the desmosomal cadherin Dsg1, or keratin IFs elevates EGFR/Erk1/2 signaling ( Getsios et al, 2009 ; Seltmann et al, 2015 ; Rubsam et al, 2017 ; Godsel et al, 2022 ). In the following sections we review how desmosomal cadherin-IF interactions participate in two major aspects of epidermal differentiation: basal cell commitment and maintenance of the TJ barrier.…”

The Epidermis: Redox Governor of Health and Diseases

“…LOF mutations in the DSG1 gene promote loss of membrane expression of DSG1, thus leading to skin dermatitis, multiple severe allergies, and metabolic wasting (SAM) syndrome [ 22 , 148 ], whose clinical features comprise striate palmoplantar keratoderma, as well as FTT and atopic manifestations similar to NS or PSS1. DSG1-knockout mice exhibit postnatal lethality due to a superficial detachment of the epidermal tissue [ 19 , 20 ], albeit exhibiting T H 17-associated inflammatory signatures at embryonic day 18.5 (right before birth) [ 20 ]. Thus, results from the rodent models and SAM syndrome patients may correspond to immunological alertness (preemptive immunity [ 41 ]) augmented by the breach of superficial epidermal tissue [ 153 ].…”

“…The earlier phase of CE assembly is mandatory for endowing the SC with waterproof property [ 2 , 15 ]. Additionally, transglutaminase 1 [ 16 ], CE precursors envoplakin/periplakin/involucrin (IVL) [ 17 ], and desmosomal components [ 18 , 19 , 20 ] appear indispensable. Findings from mouse models correlate with inborn errors in humans [ 21 , 22 , 23 ], both of which exhibit aberrantly activated immune responses [ 20 , 22 ] secondary to the compromised epidermal barrier.…”

“…Additionally, transglutaminase 1 [ 16 ], CE precursors envoplakin/periplakin/involucrin (IVL) [ 17 ], and desmosomal components [ 18 , 19 , 20 ] appear indispensable. Findings from mouse models correlate with inborn errors in humans [ 21 , 22 , 23 ], both of which exhibit aberrantly activated immune responses [ 20 , 22 ] secondary to the compromised epidermal barrier. SC’s compromised inside-out/outside-in permeability barrier function, maintained by interstitial lamellated lipids and adhesion molecules [ 24 ], has a pathogenic role.…”