The role of macrophage extracellular traps in scleroderma - systemic sclerosis - systemic sclerosis (SSC) is a devastating autoimmune disease characterized by immune dysregulation, vasculopathy, and…

The role of macrophage extracellular traps in scleroderma - systemic sclerosis - systemic sclerosis (SSC) is a devastating autoimmune disease characterized by immune dysregulation, vasculopathy, and progressive fibrosis of the skin and internal organs. Fibrosis is the principal driver of morbidity and mortality in SSC, yet the cellular and molecular mechanisms that underlie its development remain incompletely understood, and effective therapies are lacking. Neutrophil extracellular traps (nets) have been implicated in autoimmune pathogenesis, but the role of macrophage extracellular traps (mets)-a recently identified form of chromatin-based immune response-has not been explored in SSC. Preliminary data from our group demonstrate that SSC macrophages produce significantly more mets than those from healthy individuals and that met deposition is elevated in SSC skin biopsies. However, the mechanisms driving met formation and their functional role in promoting fibrosis remain unknown. This proposal tests the central hypothesis that mets are upregulated in SSC and actively contribute to fibroblast activation and fibrotic signaling through specific molecular pathways. We will address this hypothesis through two specific aims. Aim 1: define the molecular mechanisms driving increased metosis in systemic sclerosis (SSC) and its relationship to skin we will quantify mets in skin biopsies and mdms from SSC patients and matched controls, determine the involvement of PAD2/4 and ORAI1-mediated calcium influx, and explore the regulatory role of the transcription factor FLI-1 and interferon signaling. A bleomycin-induced fibrosis model will help distinguish mets from neutrophil extracellular traps (nets), enhancing mechanistic clarity. Aim 2 : determine the role of mets in promoting fibroblast activation and fibrotic signaling in SSC. We will assess the impact of mets on fibroblast activation. Met-containing conditioned media from SSC monocyte derived macrophages (mdms) will be used to stimulate primary dermal fibroblasts. Fibroblast activation and profibrotic signaling will be measured, focusing on the TLR4/TLR9-MYD88 axis and alternative pathways such as the AIM2 inflammasome. Together, these studies will uncover how mets contribute to fibrosis in SSC and identify novel therapeutic targets within macrophage-fibroblast signaling networks, advancing our understanding of fibrotic disease mechanisms.