The Journal of investigative dermatology最新文献

SLC3A2, an essential enhancer of integrin signaling, regulates skin homeostasis. We deleted SLC3A2 in hair follicle stem cells (HFSCs) to get insights into its role in cell-fate decision. Epidermal SLC3A2 is required for stem cell population maintenance. We show that slc3a2 itself is expressed in HFSCs. Deleting this gene in multiple hair follicle stem population (keratin 9, Lrig1) resulted in a drastic loss of HFSCs, leading to hair follicle growth defect. SLC3A2 is required for HFSC proper location. In the absence of SLC3A2, stem cells failed to differentiate into follicular keratinocytes; instead, they adopted an interfollicular epidermis destiny, making SLC3A2 essential for stem cell fate decisions. Hair follicle growth blockade was also associated with decreased fibronectin matrix expression. Using an in vivo skin reconstitution assay, we demonstrate that SLC3A2 preserves HFSC autonomous functions. We found that HFSC SLC3A2 integrin controls stem cell fate and skin regenerative properties, through a YAP/Taz-dependent pathway. Finally, SLC3A2 depletion in primary keratinocytes led to defective sphingomyelin synthesis and reduced CerS4 expression, showing that sphingolipid metabolism, downstream of SLC3A2, is crucial for HFSC compartment establishment.

Pemphigus vulgaris (PV) is a B-cell-mediated autoimmune blistering disease characterized by autoantibodies targeting skin cell adhesion proteins. Despite the well-defined pathophysiology and unmet need for safe and effective therapies for pemphigus, multiple therapeutics have failed to advance through clinical development. Prednisone and rituximab are clinically approved for PV, but the neonatal Fc receptor inhibitor efgartigimod and Bruton's tyrosine kinase inhibitor rilzabrutinib failed to receive clinical approval in pemphigus, despite success in other autoantibody-mediated diseases. Conversely, the success of rituximab for PV has not been reproduced for several other B cell-mediated autoimmune diseases. We review learnings from the successes and failures of rituximab, efgartigimod, and rilzabrutinib across B-cell-mediated autoimmune diseases and compare trial designs and endpoints to identify key issues affecting clinical outcomes.

Vitiligo is an acquired and polygenetic autoimmune disorder with limited effective treatments. Dermal fibroblasts play a key role in vitiligo by responding to interferon-γ (IFN-γ) and secreting chemokines to recruit and activate CD8⁺ T cells. Although narrowband ultraviolet B (NB-UVB) is a common treatment for vitiligo, it can cause side effects such as phototoxicity. This study investigated the relationship between NB-UVB and fibroblast senescence in vitiligo and the mechanisms by which NB-UVB may trigger disease progression in some cases of vitiligo. Analysis of publicly available single-cell and bulk RNA sequencing data revealed that NB-UVB irradiation induces dermal fibroblast senescence and activates both the MAPK and p53 pathways. In vitro, high-dose NB-UVB exposure leads to increased senescence and inflammation in vitiligo fibroblasts. In vitiligo mice, low-dose NB-UVB treatment significantly reduced the number of CD8⁺ T cells and increased skin pigmentation. In contrast, high-dose NB-UVB induces a senescent, proinflammatory microenvironment and exacerbates vitiligo progression in some cases. In mouse skin, high-dose NB-UVB treatment induces cell senescence, and the expression of chemokines and cytokines increases, thereby disrupting the skin microenvironment and homeostasis.