What are the causes of chronic skin inflammation?

Etiology of Chronic Skin Inflammation: A Multifactorial Process

Chronic skin inflammation results from a complex interplay between genetic predisposition, environmental factors, epithelial barrier dysfunction, and dysregulated immune responses, with environmental triggers playing a primary role in disease manifestation. 1

Genetic Factors

• Genetic susceptibility contributes to chronic inflammatory skin conditions, though genetic factors alone explain only a small portion of disease risk 1
• Multiple low-penetrance genes have been identified through genome-wide association studies, with each genetic marker typically showing weak association with disease 1
• Key genetic factors include those affecting:
  • Barrier integrity (e.g., filaggrin mutations) 2
  • Immune function regulation 2
  • Inflammatory signaling pathways 2

Environmental Triggers

• Environmental factors are the primary drivers of chronic skin inflammation, explaining the rapid increase in prevalence over the past 40-70 years 1
• Key environmental contributors include:
  • Urbanization and industrialization 2
  • Changes in dietary patterns 1
  • Reduced exposure to environmental microbial components (hygiene hypothesis) 1
  • Pollution and chemical exposures 1
  • Tobacco use 2
  • Stress 2

Epithelial Barrier Dysfunction

• Disruption of the skin's epithelial barrier is a central mechanism in chronic skin inflammation 2
• The process involves:
  • Opening of skin tight junction barriers due to genetic defects or exposure to barrier-damaging agents 2
  • Translocation of microbiota to inter- and subepithelial areas 2
  • Colonization by opportunistic pathogens (e.g., Staphylococcus aureus) 2
  • Defective epithelial barrier healing capacity due to inflammation 2
  • Creation of a vicious cycle of barrier leakiness, microbial dysbiosis, and chronic inflammation 2

Immune System Dysregulation

• Dysregulated interplay between innate and adaptive immune cells drives chronic skin inflammation 2
• Key immune components include:
  • Dendritic cells and macrophages that initiate inflammatory responses 2
  • T lymphocytes, particularly TH1, TH2, and TH17 subsets that mediate different inflammatory pathways 2
  • Innate lymphoid cells that form a link between innate and adaptive immunity 2
  • Keratinocytes that respond to and amplify inflammatory signals 2
• The IL-23/TH17 pathway plays a central role in many chronic inflammatory skin conditions 2

Microbiome Influence

• The skin microbiome acts as an intermediary between the organism and environment 1
• Microbial dysbiosis and decreased biodiversity of commensal organisms contribute to chronic inflammation 2
• The diversity of microbial exposure during childhood is inversely related to risk of inflammatory skin conditions 1

Epigenetic Modifications

• Epigenetic changes provide a crucial link between environmental influences and disease development 1
• Prenatal exposures can produce epigenetic modifications that act alongside genetic predisposition to determine biological responses to environmental stimuli 1
• Micro-RNAs affected by environmental factors play a role in regulating immune responses 2

Systemic Inflammation

• Chronic skin inflammation often involves systemic inflammatory processes 2
• This explains the association between inflammatory skin diseases and comorbidities such as cardiovascular disease, metabolic syndrome, and other immune-mediated conditions 2

The etiology of chronic skin inflammation represents a complex interplay of factors, with environmental triggers acting upon genetic susceptibility, leading to epithelial barrier dysfunction, immune dysregulation, and perpetuation of inflammatory processes that become self-sustaining over time.