RAB25 coordinates filaggrin‐containing keratohyalin granule maturation and affects atopic dermatitis severity

Abstract

Background: Keratohyalin granules (KHGs) supply the critical epidermal protein constituents such as filaggrin for maintaining skin barrier function during epidermal differentiation; however, their regulating mechanism remains largely unelucidated. Methods:To investigate the role of Ras-related protein Rab-25 (RAB25) expression in skin disease, we utilized skin specimens of patients with moderate-to-severe atopic dermatitis (AD) and healthy controls. To investigate the susceptibility of Rab25 knockout mice to AD, we established an oxazolone-induced AD model. Results:We investigated the role of RAB25 in KHG maturation and AD. RAB25deficient mice showed a disrupted stratum corneum along with skin barrier dysfunction, decreased KHG production, and abnormal KHG processing. Consistently, in the human keratinocyte cell line HaCaT, RAB25 co-expressed with filaggrin-containing KHG and RAB25 silencing impaired KHG formation, which was attributable to abnormal actin dynamics. Most importantly, RAB25 expression was severely downregulated in the skin lesions of patients with AD, which was strongly correlated with disease severity scores.Conclusions: RAB25 coordinates KHG homeostasis by regulating actin dynamics and is critical for epidermal differentiation and the pathophysiology of AD.

Biomarkers for phenotype-endotype relationship in atopic dermatitis: a critical review

“…RAB25, a promising severity biomarker, represents epidermal barrier function impairment in AD. 54 Recent study have shown that RAB25 expression in the skin is significantly lower in patients with AD. Moreover, RAB25 expression negatively correlated with the EASI score.…”

“…It denotes an immunological hypersensitivity to Malassezia species Severity biomarker, Endotypic biomarker 48 , 49 Eosinophil counts, ECP Releases eosinophil basic proteins upon activation via Th2 cytokines Monitoring biomarker 50 , 51 Soluble IL-2R Soluble cytokine receptor which secreted upon T-cell activation. Elevated serum levels are observed across a range of immune-related conditions Monitoring biomarker 29 , 30 S100A7/A8/A9//A12 Anti-microbial peptides; preferentially kills E. coli Severity biomarker, 9 , 38 , 52 , 53 E-selectin Allows the adhesion of neutrophils, monocytes, and leukocytes on stimulated endothelium in the skin Monitoring biomarker 10 , 28 RAB25 A member of the RAB11 small GTPase subfamily, which orchestrates intracellular vesicle trafficking Severity biomarker 54 MMP8, 9, 12 Protease involved in macrophage migration, could also have a crucial role in regulating the resolution of inflammation Severity biomarker 10 , 38 , 41 , 55 LDH Tetrameric oxidoreductase enzyme; non-specific marker of tissue turnover Severity biomarker, Monitoring biomarker 28 , 56 CA II Carbonic anhydrase catalyses the reversible hydration of carbon dioxide Diagnostic biomarker 57 , 58 NELL2 Important for neuronal polarization and axon growth Diagnostic biomarker 58 EDN Secretory proteins of eosinophils, it has broad antiviral activity, targets RNA viruses …”

“…Along with clinical data, RAB25 was co-expressed with filaggrin, indicating that RAB25 is a promising severity biomarker that reflects the key pathogenesis of AD. 54 …”