ICOS/ICOSL upregulation mediates inflammatory response and endothelial dysfunction in type 2 diabetes mellitus

Area of Science:

• Immunology and Endocrinology
• Molecular Biology
• Vascular Biology

Background:

• Inducible T-cell costimulator (ICOS) and its ligand (ICOSL) are key in immune responses.
• The specific role of ICOS/ICOSL in type 2 diabetes mellitus (T2DM) remains unclear.
• Understanding ICOS/ICOSL's function in T2DM is crucial for addressing related complications.

Purpose of the Study:

• To investigate the role of ICOS/ICOSL in the pathogenesis of type 2 diabetes mellitus (T2DM).
• To explore the impact of high glucose (HG) and advanced glycation end products (AGEs) on ICOS/ICOSL expression.
• To assess the effect of ICOS/ICOSL blockade on cellular responses in a T2DM model.

Main Methods:

• Human peripheral blood T-lymphocytes (CD3) and umbilical vein endothelial cells (HUVECs) were exposed to HG or AGEs.
• Co-culture experiments with T cells and HUVECs were performed, with and without anti-ICOS monoclonal antibodies (mAbs).
• Protein expression (ICOS/ICOSL, caspase-3), cytokine levels (IFN-γ, IL-4, IL-10, IL-6, IL-8), cell viability (MTT assay), and NOx production were measured.

Main Results:

• HG and AGEs significantly increased ICOS/ICOSL expression in T cells and HUVECs.
• T cell-HUVEC co-culture led to increased secretion of IFN-γ, IL-4, and IL-10, while IL-6 and IL-8 increased in HUVECs.
• Blocking ICOS/ICOSL reduced cytokine secretion, enhanced cell viability, and decreased caspase-3 and NOx production.

Conclusions:

• High glucose and AGEs induce T cell inflammatory responses and vascular endothelial dysfunction via ICOS/ICOSL upregulation.
• This ICOS/ICOSL pathway represents a potential mechanism underlying cardiovascular complications in T2DM.
• Targeting ICOS/ICOSL may offer a therapeutic strategy for managing T2DM-associated vascular issues.