Peripheral neuropathy plays a role in chronic diabetic foot ulcers (DFUs), also leading to an imbalance in inflammation, as pro-inflammatory macrophages (M1) have difficulty switching to an anti-inflammatory phenotype (M2) contributing to a chronic inflammatory phase and healing impairment. Protein tyrosine phosphatase 1B (PTP1B), in the skin, is over expressed in diabetes and DFUs. We aimed to evaluate the role of PTP1B inhibition in macrophage under high glucose conditions. THP-1 monocytic cells were differentiated into macrophages, treated with the PTP1B inhibitor MSI-1436 (1 µM) and stimulated with LPS for 24h, under high glucose (25 mM) or normoglycemic conditions (5.5 mM). Cell viability was measured by MTT assay. The numbers of M1 and M2 macrophages were evaluated by immunocytochemistry by double staining with CD68 and TNF-α for M1 macrophages, and CD68 and CD163 for M2 macrophages. In addition, pro-inflammatory cytokine expression was analyzed by qRT-PCR. Oxidative stress was assessed by the DCFH-DA assay, heme oxygenase-1 (HO-1) enzyme levels were also measured by immunocytochemistry and Western blot. The treatment with MSI-1436 did not alter THP-1 cell viability. In inflammatory conditions (LPS), THP-1 cells grown under HG and treated with MSI-1436 showed an increase in M2 macrophages and a reduction in M1 macrophages (246 ± 26% and 102 ± 9%, p<0.05, of LPS treated cells, respectively). In addition, PTP1B inhibition induced a decrease in pro-inflammatory cytokine expression, IL-6, IL-1β and MCP-1, a decrease in ROS levels (78 ± 10% of LPS treated cells) and an increase in HO-1 expression (290 ± 23%, p<0.05, of LPS treated cells). Inhibition of PTP1B in macrophages, under high glucose conditions, promotes a significant reduction in the inflammatory environment and oxidative stress via increase of HO-1 expression, suggesting that PTP1B is a potential therapeutic target for the treatment of chronic DFUs.


A. Figueiredo: None. E.C. Leal: None. D. Santos: None. G. Gasiunaite: None. M. Delibegovic: None. E. Carvalho: None.


Diabetes UK; Portuguese Foundation for Science and Technology; European Foundation for the Study of Diabetes; Portuguese Society of Diabetology

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