Envenomation by Loxosceles spiders produces a condition termed loxoscelism, which may manifest in cutaneous and systemic forms. Cutaneous loxoscelism is characterized by intense inflammation and dermonecrosis, driven mainly by phospholipase D (PLD) toxins in Loxosceles venom. This study investigated the molecular mechanisms and cellular contributions underlying these effects. Human dermal and epidermal cells, including keratinocytes, fibroblasts, and endothelial cells, were used. Recombinant PLD from L. intermedia venom, LiRecDT1, was employed as the toxin model. Functional assays evaluated leukocyte adhesion to endothelial cells exposed to LiRecDT1 and toxin-treated media from keratinocytes and fibroblasts. Further analysis explored a systems biology approach to model cellular signaling networks activated by PLDs. Finally, the cells were exposed to LiRecDT1, and gene expression was quantified via RT-qPCR to assess cellular responses. LiRecDT1 and conditioned media from treated keratinocytes and fibroblasts promoted leukocyte adhesion to endothelial cells. Based on in silico predictions, key pathway nodes were identified and validated experimentally. The increased expression of inflammatory mediators IL-1β, IL-6 and cellular stress TNF-α genes in all cells peaked at 4h, consistent with a pattern of acute inflammation. Cell-type-specific differences became apparent by 24h in the distinct modulation of STAT3, IL1β, TNF-α and AKT1, as well as in the unexplored targets RELA, TP53, STAT3, and c-JUN. Prolonged exposition to the toxin demonstrated modulation of some of these pathways related to chronic/unresolved inflammation, immune modulation and fibrotic remodeling. These findings highlight the coordinated contributions of skin-resident cells to cutaneous loxoscelism and highlight novel potential targets for therapeutic intervention.

The pancreatic islet, historically described as a binary system of insulin-secreting beta cells and glucagon-secreting alpha cells, is increasingly recognized as a complex paracrine network contributing to glucose homeostasis. Alpha-to-beta cell communication is not merely modulatory but a decisive mechanism sustaining islet function under metabolic stress. Alpha cell distribution, structural specializations at the alpha-beta interface, and adaptations in signaling pathways collectively shape glycemic set points and beta cell resilience. Recent studies highlight the context-dependent nature of this intra-islet crosstalk. Visa et al. demonstrated that prediabetic stress in Western diet-fed mice remodels islet cytoarchitecture in a sex-dependent manner, enhancing alpha-to-beta signaling and Ca2+ dynamics, and thereby preserving insulin secretion more effectively in females than in males. Experiments using a glucagon receptor antagonist in human islets confirmed that glucagon paracrine signaling is essential for this adaptive enhancement, particularly the increased Ca2+ dynamics in female islets under high metabolic demand. Mechanistic studies further revealed that the GLP-1 receptor forms specialized nanodomains at the alpha-beta junction that undergo pre-internalization, priming beta cells for rapid Ca2+ influx and heightened metabolic responsiveness. Collectively, these findings highlight intra-islet communication as a critical determinant of adaptation or failure in diabetes progression. However, conflicting evidence from beta cell-only islets, which display enhanced glucose-stimulated insulin secretion, together with reports that long-term exposure to the GLP-1 analog liraglutide can compromise beta cell function, presents a paradox that challenges current models of intra-islet regulation. Understanding these nuances is crucial for translating intra-islet signaling into targeted therapeutic strategies and regenerative tissue engineering.