Humoral responses in skin inflammation resulted from altered expression of epidermal Blimp-1 2308147

Introduction The skin epithelium provides both physical and immunological barriers essential for host defense. Our previous study demonstrated that inducible epidermal deletion of Prdm1 (encoding Blimp-1) in K5-CreER+Prdm1^f/f mice on a C57BL/6 background resulted in granulocyte-dominated chronic dermatitis, establishing Blimp-1 as a key regulator of epidermal immunity. However, the immunoregulatory role of keratinocyte-intrinsic Blimp-1, particularly in epithelial—immune and host—microbe interactions, remains largely unexplored. Moreover, the mechanisms underlying humoral immune responses during skin inflammation are still unclear. Methods To investigate how epidermal Blimp-1 regulates keratinocyte immune responses and humoral immunity, we generated mice with epidermal-specific deletion of Prdm1 on a BALB/c background, which is prone to type 2 humoral immune responses. In parallel, a high-throughput screening (HTS) platform using Prdm1^YFP/+ reporter keratinocytes was established to identify compounds that modulate Blimp-1 expression. Results Prdm1-deficient keratinocytes exhibited synergistic upregulation of the alarmin thymic stromal lymphopoietin (TSLP) upon Staphylococcus aureus challenge. Consistently, conditional knockout (CKO) mice developed a dominant type 2 immune milieu characterized by elevated IL-4, IL-13, and TSLP expression. This epithelial immune dysregulation was associated with staphylococcal dysbiosis, marked by Staphylococcus sciuri overgrowth, and induced robust production of S. sciuri—specific IgG1 and IgG2b antibodies. HTS of a 9,000-compound library identified several candidate compounds capable of modulating Blimp-1 expression. Conclusion These findings indicate that epidermal Blimp-1 constrains type 2 inflammation and humoral immune responses during microbial exposure. Ongoing studies will determine how Blimp-1 suppresses keratinocyte-derived TSLP production and whether identified compounds can restore epithelial immune homeostasis in atopic dermatitis models. Funding Source n/a Topic Categories Immediate Hypersensitivity, Asthma, and Allergic Responses (HYP)