The Role of VGLL3 in Sexually Dimorphic Interferon-Driven Inflammation

This study investigates the molecular basis for female-biased susceptibility to autoimmune diseases by examining sex differences in human skin transcriptomes and identifying a VGLL3-regulated inflammatory network. Autoimmune diseases affect an estimated 7.5% of the U.S. population and disproportionately impact women; approximately 78% of affected individuals are female and female-to-male prevalence ratios can be striking (for example, systemic lupus erythematosus at 9:1 and systemic sclerosis at 11:1). To explore mechanisms beyond sex hormones, the authors performed high-resolution global transcriptome analyses on skin biopsies from healthy donors (31 female and 51 male samples) using whole-genome RNA sequencing. They identified 661 genes differentially expressed between sexes (FDR ≤ 0.1), with 393 genes upregulated in females and 268 upregulated in males. This female-biased molecular signature was linked to broader sex-dependent co-expression networks involving immune processes such as complement activation and phagocytosis.

Among sex-biased transcription factors, VGLL3 emerged as a critical regulator driving female-biased inflammatory gene expression. VGLL3 itself showed strong female-biased expression and regulated genes implicated in autoimmune pathogenesis, including BAFF/TNFSF13B and ITGAM (encoding the integrin αM), the latter being a genetic risk factor for SLE and the former an important modulator of B cell survival. On a genome-wide level, genes targeted by VGLL3 showed strong associations with multiple autoimmune diseases, including lupus, systemic sclerosis, and Sjogren's syndrome, and had a notable transcriptomic overlap with inflammatory processes observed in cutaneous lupus. Functional assays indicated that VGLL3 is required for an optimal interferon (IFN) response in monocytes and salivary gland cells, linking VGLL3 to interferon-driven inflammation - an axis central to many autoimmune conditions. Importantly, the identified female-biased signature and VGLL3 regulation appeared independent of biological age and sex-hormone regulation, suggesting a sex-hormone - independent mechanism that predisposes females to autoimmunity. The study underscores the value of examining immunological processes separately in females and males and points to VGLL3 and its downstream network as potential targets for therapeutic development.

By connecting skin-based sex differences in transcriptomes to systemic autoimmune risk and demonstrating VGLL3's role in modulating interferon responses and key inflammatory mediators, Liang and colleagues provide a mechanistic foundation for future investigations into sex-biased autoimmunity and for designing interventions that account for sex-specific disease biology. The findings highlight skin as a sentinel tissue for immune dysregulation and suggest new avenues for targeted therapies that could mitigate female-biased autoimmune susceptibility by modulating VGLL3-driven pathways.