RESUMEN
Patients with glycogen storage disease type Ib (GSD-Ib) frequently have inflammatory bowel disease (IBD). however, the underlying etiology remains unclear. Herein, this study finds that digestive symptoms are commonly observed in patients with GSD-Ib, presenting as single or multiple scattered deep round ulcers, inflammatory pseudo-polyps, obstructions, and strictures, which differ substantially from those in typical IBD. Distinct microbiota profiling and single-cell clustering of colonic mucosae in patients with GSD are conducted. Heterogeneous oral pathogenic enteric outgrowth induced by GSD is a potent inducer of gut microbiota immaturity and colonic macrophage accumulation. Specifically, a unique population of macrophages with high CCL4L2 expression is identified in response to pathogenic bacteria in the intestine. Hyper-activation of the CCL4L2-VSIR axis leads to increased expression of AGR2 and ZG16 in epithelial cells, which mediates the unique progression of IBD in GSD-Ib. Collectively, the microbiota-driven pathomechanism of IBD is demonstrated in GSD-Ib and revealed the active role of the CCL4L2-VSIR axis in the interaction between the microbiota and colonic mucosal immunity. Thus, targeting gut dysbiosis and/or the CCL4L2-VISR axis may represent a potential therapy for GSD-associated IBD.
RESUMEN
OBJECTIVE: In patients with peripheral artery disease, blockages in arterioles <1 mm cannot be treated surgically, and there are currently few effective medicines. Studies have shown that inflammation in ischemic tissue is related to injury recovery and angiogenesis, but insufficient attention has been paid to this area. Studies have suggested that HMGB1 (high mobility group protein 1), which is released by ischemic tissue, promotes angiogenesis, but the mechanism is not entirely clear. In this study, we tested the internalization of HMGB1 in endothelial cells and investigated a novel proangiogenic pathway. Approach and Results: Using green fluorescent protein-tagged HMGB1 to stimulate endothelial cells, we demonstrated HMGB1 internalization via dynamin and RAGE (receptor for advanced glycation end products)-dependent signaling. Using a fluorescence assay, we detected internalized protein fusion to lysosomes, followed by activation of CatB (cathepsin B) and CatL (cathepsin L). The latter promoted the release of VEGF (vascular endothelial growth factor)-A and endoglin and upregulated the capacities of cell migration, proliferation, and tube formation in endothelial cells. We identified that the cytokine-induced fragment-a key functional domain in HMGB1-mediates the internalization and angiogenic function of HMGB1. We further confirmed that HMGB1 internalization also occurs in vivo in endothelial cells and promotes angiogenesis in mouse femoral artery ligation. CONCLUSIONS: In this study, we identified a novel pathway of HMGB1 internalization-induced angiogenesis in endothelial cells. This finding sheds light on the regulatory role of inflammatory factors in angiogenesis through cell internalization and opens a new door to understand the relationship between inflammation and angiogenesis in ischemic diseases.