OTULIN's Role In Skin Homeostasis And Keratinocyte Regulation.pdf

- Study: Hoste et al. investigate OTULIN's role in skin homeostasis.
- Method: Keratinocyte-specific OTULIN deletion (ΔKerOTULIN) in mice.
- Findings:
- ΔKerOTULIN mice develop severe skin inflammation, compromised barrier, increased cell death.
- TNFR1 ablation, RIPK1 inhibition, or MLKL/FADD deletion in keratinocytes prevents skin inflammation.
- Single-cell RNA-seq reveals IFN and IL-1β signaling in inflamed skin.
- IFNAR1-/- x ΔKerOTULIN mice show reduced inflammation; anti-IL-1β antibody treatment helps.
- OTULIN L272P mutation, equivalent to a human loss-of-function mutation, causes embryonic lethality and skin inflammation.
- Reviewer Comments:
- Well-written, well-designed study with solid conclusions.
- Major Points:
1. Discuss TNF-independent pathways driving inflammation.
2. Standardize figure magnification and aspect ratio.
3. Clarify serum cytokine data reuse and comparability.
4. Provide evidence for proteasomal degradation of LUBAC components.
5. Clarify OTULIN levels and reproducibility in ΔKerOTULIN mice.
6. Specify skin layers used for single-cell analysis and address T-cell discrepancy.
7. Discuss IFNAR1-/- mice's immune defects in context of ΔKerOTULIN x IFNAR1-/- findings.