Inflammatory and diabetic conditions trigger SHP2 tyrosine phosphatase expression and subsequent aberrant activation of primary human monocytes

Abstract Purpose Atherosclerosis is an inflammatory process that particularly accelerated in diabetics, leading to increased incidence of cardiovascular diseases such as CAD and PAD diabetic patients. Monocytes are the main component atherosclerosis development. SHP-2 tyrosine phosphatase has been identified important regulator monocyte function. The present study therefore aims investigate regulation conditions. Methods Primary human monocytes were isolated from peripheral blood type 2 Diabetes mellitus (T2DM) patients healthy individuals. incubated with pro-inflammatory cytokine TNFa. For conditions, methylglyoxal (MG), a highly reactive side product glycolysis, or Receptor for advanced glycation end (RAGE) ligand AGE-bovine serum (AGE-BSA). Monocyte migration was studied Transwell assays. Expression molecules investigated Western Blot, RT-qPCR FACS. Pharmacological inhibitors SHP2, RAGE NFκB used. Results First, we could detect significant correlation between mRNA TNFa levels T2DM comparison In line that, incubation lead enhanced expression SHP-2. Co-incubation NFκB-inhibitor blocked TNFa-induced upregulation. Interestingly, caused release also augmented SHP-2, indicating effect Moreover, AGE-BSA treatment induced expression, reflecting inflammatory-independent pathway which regulates additionally. This be supported by observation pharmacological inhibition attenuated both MG-induced activation. On functional level, each resulted pro-migratory phenotype completely reversed RAGE, respectively. Fittingly, showed migration, normalized ordinary level after application inhibitor. Conclusions results reveal new mechanism development MG glycated products, crucial components milieu, via RAGE-NFkB signalling axis. this environment causes response through cytokine, itself leads activation NFkB transcription factor. Finally, outlined regulatory pathway, able prevent monocytes, offering approach diabetes-induced atherosclerosis. Funding Acknowledgement Type funding sources: Other. Main source(s): IZKF SEED Project 14/20