Not to be ignored: The involvement of the G-protein coupled formylpeptide receptors in high glucose-promoted progression of metabolic diseases and glioblastoma

Hyperglycemia is linked to many inflammatory, metabolic and malignant diseases. High glucose provides inflammatory and cancer cells with more abundant “fuel” that promotes the cell motility, proliferation and production of pro-inflammatory mediators. The “malicious behavior” of activated inflammatory cells and cancer cells is further exacerbated by over-expression of chemoattractant receptors, notably FPRs (mouse Fprs) and tyrosine kinase receptors (TKRs) that are traditionally discovered as mediators of cell migration in response to a number of pathogen and host-derived chemotactic molecular patterns (PMAPs and DAMPs) existing at the diseased sites. In addition, the M1 macrophage polarizing capacity of one of FPRs, Fpr2, acts as a double-edged sword that exacerbates the insulin resistance and obesity in high-fat diet-fed mice. Therefore, while controlling glucose to a physiological level is important, targeting cell surface FPRs and TKRs should also be critical to manage hyperglycemia-associated disease conditions. Müller glial cells, an FPR variant FPR2 (Mouse Fpr2) mediates increased cell chemotaxis, thus recruitment, and proliferation in the retina, in response to an endogenous Fpr2 agonist peptide CRAMP. This process exacerbates the inflammatory conditions and the progression of diabetic retinopacy. In human glioblastoma cells, HG increases the expression and function of the prototype formylpeptide receptor FPR1, which promotes tumor cell invasion, proliferation and production of the angiogenic factor vascular endothelial cell growth factor (VEGF), by interaction with an agonist Annexin 1 (Anx A1) released by necrotic tumor cells. HG also elevates the expression and function of EGFR on glioblastoma cells and bFGFR on Müller cells. Both TKRs cooperation with FPRs to promote cell chemotaxis and proliferation. of the function of chemoattractant receptor FPR1 and the growth factor receptor