IF isotretinoin (10 mg/kg/day, oral gavage) is administered for 8 weeks to 24-month-old C57BL/6 mice preceded by a 2-week anti-inflammatory preconditioning phase using a JAK1/2 inhibitor (ruxolitinib, 30 mg/kg/day oral gavage) to arrest ongoing inflammation-driven lamin-B1 degradation in thymic epithelial cells (TECs),

THEN a synergistic ≥2-fold expansion of functional cTEC (MHCIIhiUEA-1−) and mTEC (MHCIIhiUEA-1+AIRE+) populations, ≥50% restoration of FOXN1 protein in sorted TECs, ≥30% increase in thymic mass, and ≥40% rise in TREC+ naive CD4+CD62L+CD44− T cells in peripheral blood versus aged vehicle controls will be observed at week 10 — outcomes unachievable by isotretinoin monotherapy —

BECAUSE the following causal chain operates sequentially:

1. Chronic thymic inflammation in aged mice drives progressive, cell-type-specific lamin-B1 loss in TECs, causing disrupted corticomedullary architecture, loss of TEC subset composition, impaired thymopoiesis, and a perivasculitis-like inflammatory microenvironment — establishing that nuclear lamina structural damage is an upstream, accumulated lesion in aged TECs, not merely a correlate of FOXN1 decline. (Lamin-B1 in TEC aging)[https://doi.org/10.1111/acel.12952]

2. Lamin-B1 depletion repositions genes including Foxn1 toward lamina-associated repressive domains (LADs), closing chromatin accessibility at RAR/RXR response element–containing regulatory regions of the Foxn1 promoter/enhancer. This means that even if retinoic acid receptors are pharmacologically activated by isotretinoin, they cannot access a Foxn1 locus sequestered in perilaminar heterochromatin. [SPECULATIVE — no direct ChIP-seq evidence for Foxn1-LAD repositioning in aged TECs exists yet, but is mechanistically predicted from lamin-B1 biology; see gaps below.]

3. JAK1/2 inhibition arrests the upstream inflammatory signaling (IFN-γ, IL-6, TNF) that drives ongoing lamin-B1 proteolysis in aged TECs, halting further nuclear lamina damage and allowing partial lamin-B1 reaccumulation in the surviving TEC progenitor pool during the preconditioning window. This converts the chromatin state from a closed, LAD-sequestered configuration to one that is permissive for RAR/RXR binding at Foxn1 regulatory elements. (Inflammation-driven lamin-B1 reduction in thymus aging)[https://doi.org/10.1111/acel.12952]

4. Subsequent isotretinoin administration activates RAR/RXR signaling on the now-accessible Foxn1 promoter, driving transcriptional upregulation of FOXN1 protein in residual cTEC/mTEC progenitors. This mirrors the principle demonstrated by FOXN1-reprogramming strategies: restoring FOXN1 activity in the aged thymic stromal compartment is sufficient to rebuild cortical and medullary architecture. (FREF-mediated FOXN1 restoration rejuvenates aged thymic architecture, restoring K5+ medullary and K8+ cortical compartments)[https://doi.org/10.1172/jci.insight.140313]

5. **FOXN1 re-expression in progenitor TECs drives proliferativ...

SENS category: RepleniSENS

Key references: • doi.org/10.1111/acel.12952] • doi.org/10.1172/jci.insight.140313] • doi.org/10.4049/jimmunol.1403158] • doi.org/10.1101/2024.10.23.619838] • doi.org/10.1016/j.exger.2017.12.022]