Nguyen Thi Kim Nguyen

For patients with systemic lupus erythematosus (SLE), sun avoidance and sunscreen use are the only preventive therapies for photosensitivity, a process by which exposure to ultraviolet (UV) light triggers cutaneous and systemic flares of disease. Photosensitivity is exceedingly common among patients with SLE who develop rashes, affecting up to 93% of this population. Treatment of skin and systemic disease triggered by the sun can be challenging, and thus there exists a critical need for better therapeutic and preventative strategies. Innovation of targeted therapies for photosensitive skin diseases requires a precise dissection of the cellular players and signaling pathways that contribute to aberrant inflammation after UV exposure. Here, we used cutaneous UVB photoexposure of healthy controls and patients with SLE to provide an atlas of the cutaneous inflammatory response 24 hours after UV exposure in single-cell resolution. We demonstrate that the epidermis is dysregulated in lupus, where epidermal-dermal cross-talk in SLE is dominated by inflammatory keratinocytes after UV exposure in contrast with the healthy control epidermis. In both healthy controls and patients with SLE, the downstream consequence of UV exposure is the recruitment of a population of monocyte-derived dendritic cells (moDCs). Although moDCs are present in relatively equal proportions in SLE and healthy control UV-treated skin, they appear to be derived from distinct circulating monocyte populations. SLE UV moDCs are characterized by inflammatory and antigen presentation pathways and may represent a precursor to lesional cutaneous lupus CD16 ⁺ DCs, identifying a potential link between cutaneous UV responses and cutaneous lupus flare.

The interfollicular epidermis is maintained by spatially organized basal cell populations with distinct molecular signatures and division kinetics; however, the markers that define these populations remain poorly defined. In this study, we identified Il1r2, which encodes the IL-1 decoy receptor IL-1R2, as a marker of the slow-cycling basal population in the epidermis. Single-cell RNA-seq analysis of epidermal and hair follicle basal populations in the murine tail skin revealed that Il1r2 is preferentially expressed in the slow-cycling epidermal basal population, and immunofluorescence staining confirmed its protein localization in tissues. To enable fate mapping of this population, we generated an Il1r2-CreERT2 knock-in mouse line using a CRISPR-Cas9-based PITCh method. Tamoxifen induction in Il1r2-CreERT2/Rosa-tdTomato mice exhibited selective labeling of basal cells localized to the slow-cycling interscale region of the tail epidermis. Because the CreERT2 cassette was inserted into the Il1r2 coding sequence, homozygous Il1r2-CreERT2 knock-in mice can also serve as an Il1r2 knockout model through targeted gene ablation. Thus, the Il1r2-CreERT2 mouse line provides a dual genetic tool for lineage tracing of the slow-cycling epidermal basal population and for functional modulation of IL-1 signaling in vivo.

Basal keratinocytes in the skin are essential for epidermal homeostasis and repair; however, how intrinsic alterations in these cells contribute to inflammatory skin pathology remains poorly understood. In this study, we employed a tamoxifen-inducible mouse model to express the human RUNX1-ETO fusion gene, a well-established oncogenic driver of acute myeloid leukemia, in epidermal basal keratinocytes. RUNX1-ETO induction in keratinocytes resulted in progressive skin inflammation in vivo, accompanied by splenomegaly, epidermal hyperplasia, increased cytokine production, and alterations in epidermal stem cell composition. Inflammatory lesions were prominent in the tail, ear, and plantar epidermis, whereas hair-bearing dorsal skin remained largely unaffected. RNA-seq analysis of FACS-isolated RUNX1-ETO+ basal keratinocytes revealed global changes in gene expression, characterized by the suppression of epidermal homeostatic and metabolic programs and the activation of inflammatory signaling pathways. In particular, RUNX1-ETO expression was associated with increased TNF/NF-kB and IL-6-STAT signaling, as well as interferon-associated inflammatory pathways, together with the induction of neutrophil-attracting chemokines and epithelial inflammatory mediators. Together, these findings indicate that RUNX1-ETO-mediated transcriptional dysregulation in basal keratinocytes promotes a pro-inflammatory cellular state that drives progressive skin inflammation.

The skin epidermis is maintained by spatially organized stem cell populations with distinct cellular dynamics; however, how inflammation affects this heterogeneity remains largely unknown. Here, we demonstrate that acute skin inflammation alters epidermal stem cell compartments through IL-1-mediated suppression of canonical Wnt signaling. Lineage tracing in inflamed mouse skin revealed that slow-cycling Dlx1+ epidermal stem cell clones persist, whereas fast-cycling Slc1a3+ clones decline through enhanced differentiation and lineage conversion, driving the reorganization of epidermal stem cell compartments. IL-1 signaling is both necessary and sufficient for this change: administration of IL-1 recapitulates these effects, while transgenic induction of the IL-1 decoy receptor preserves the balance of stem cell populations. IL-1 suppresses canonical Wnt activity in both the mouse epidermis and human keratinocytes, and Wnt ligand administration restores the fast-cycling compartment in vivo. Together, these results identify a reversible IL-1-Wnt axis that governs inflammation-induced stem cell plasticity and spatial tissue remodeling.