Keratinocytes Drive Inflammatory Skin & Mucosal Disorders
Publication Title: Keratinocytes as active regulators of cutaneous and mucosal immunity: a systematic review across inflammatory epithelial disorders
Summary
- Question
- This study systematically reviewed the role of keratinocytes, the predominant cell type in the skin's outer layer, as active regulators of immunity in inflammatory epithelial disorders. The researchers examined keratinocyte-driven immune mechanisms across six common skin and mucosal conditions: atopic dermatitis, psoriasis, lichen planus, bullous pemphigoid, lupus erythematosus, and graft-versus-host disease.
- Why it Matters
- Understanding keratinocytes' immune functions is critical because these cells are more than structural components—they actively shape immune responses. Their role in conditions such as eczema, autoimmune diseases, and transplant-related inflammation could reveal therapeutic targets to reduce chronic inflammation and improve treatment strategies for skin and mucosal diseases. Insights from this research can benefit clinicians, researchers, and patients by advancing precision medicine and improving care for these widespread disorders.
- Methods
- The researchers conducted a systematic review using PRISMA guidelines, analyzing 82 studies from databases such as MEDLINE, EMBASE, and CENTRAL. The studies included human, cell culture, and animal models, focusing on keratinocyte immune functions, signaling pathways, and tissue-specific responses in skin and mucosa.
- Key Findings
- Keratinocytes were found to produce inflammatory molecules like cytokines (e.g., IL-1b, IL-6, TNF-a, IL-33) and recruit immune cells, acting as nonprofessional antigen-presenting cells. Common activation pathways included NF-kB, JAK/STAT, and MAPK signaling. Disease-specific patterns emerged: Th2-driven inflammation in atopic dermatitis and bullous pemphigoid; Th1/Th17 responses in psoriasis and lichen planus; and type I interferon responses in lupus and graft-versus-host disease. Stress keratins (e.g., KRT6, KRT16, KRT17) amplified inflammatory signals and were linked to immune dysregulation.
- Implications
- These findings position keratinocytes as central players in inflammatory skin and mucosal disorders. Their active role in immune signaling suggests new therapeutic opportunities, such as targeting keratinocyte-specific pathways or stress keratins to reduce inflammation and tissue damage. Differentiating keratinocyte functions in skin versus mucosa can guide tailored interventions for diverse diseases.
- Next Steps
- The authors recommend future research to create a unified keratinocyte atlas using single-cell and spatial transcriptomics. Additional studies should explore keratinocyte responses in mucosal tissues, environmental factors like microbiome and UV exposure, and early disease stages. Targeting pathways like JAK/STAT or stress keratins could advance disease-specific treatments.
- Funding Information
- This research was supported by the German Research Foundation (DFG) grant KL 3846/2-1 and the National Institutes of Health (awards R01HL127349, R01HL141852, U01HL145567, R21HL161723, P01HL11450, and U01HL148860). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Full Citation
Klimitz F, Shen Y, Repetto F, Brown S, Knoedler L, Ko C, Abu Hussein N, Crisler W, Adams T, Kaminski N, Lian C, Murphy G, Hsia H, Pomahac B, Kauke-Navarro M. Keratinocytes as active regulators of cutaneous and mucosal immunity: a systematic review across inflammatory epithelial disorders. Frontiers In Immunology 2025, 16: 1694066. PMID: 41479908, PMCID: PMC12753988, DOI: 10.3389/fimmu.2025.1694066.
This AI-assisted summary has been reviewed and approved by at least one of the study's authors to ensure it accurately reflects the research.
Authors
Felix J. Klimitz
First AuthorMartin Kauke-Navarro, MD
Last AuthorHospital Resident