CARD9 mediates T1D by reshaping macrophage function through sensing the pancreatic islet sympathetic nervous system 4832

Abstract Description Type 1 diabetes (T1D), an autoimmune disorder, causes specific damage to pancreatic islet beta cells, leading to the selective loss of sympathetic neurons in the endocrine part of the pancreas during the early stages, while sympathetic neurons in the exocrine part surrounding the islet are preserved. This abnormal sympathetic nervous signaling may disrupt the balance of the neuroendocrine-immune network and contribute to the development of T1D, but its underlying molecular mechanisms remain unclear. Here, we demonstrate the critical role of CARD9, a signaling node in pancreatic macrophages, in sensing the selective loss of the pancreatic sympathetic nervous system during the pathogenesis of T1D. Single-cell omics and whole-tissue immunostaining reveal a decrease in pancreatic sympathetic nerve density in T1D patients and various T1D mouse models. Surgical and chemical desensitization of the sympathetic nervous system exacerbated T1D, whereas macrophage depletion reduced this effect. Using pharmacological and genetic tools, we show that reduced NE secretion due to sympathetic nervous loss triggers pro-inflammatory macrophage activation by inhibiting the PKA/CREB1/CARD9 pathway, promoting the onset and progression of T1D. This study comprehensively elucidates how CARD9 senses sympathetic nervous signals to reshape macrophage function during T1D progression, offering new insights for clinical T1D treatment. Funding Sources The study is supported by the National Natural Science Foundation of China (Grant Nos. 82371824). Topic Categories Neuroimmunology (NEUR)