Can CD44 Be a Mediator of Cell Destruction? The Challenge of Type 1 Diabetes
Fig 5
Three CD44-dependent pathways affect the fate of T1D in NOD mice. I. CD44 involvement in inflammatory cell migration (blue). Inflammation upregulates CD44 on the islet-infiltrating cells. The firm adhesion of the CD44 receptor to the HA substrate slows the motility of the inflammatory cells on the endothelium. II. CD44 involvement in peripheral insulin sensitivity and glucose uptake (green). CD44 expression on peripheral tissue, increases insulin sensitivity and glucose uptake by, for example, muscle and liver cells, resulting in reduced hyperglycemia. Compensation for insulin-deficiency (see pathway III) may explain this event. III. CD44 involvement in β cell apoptotic death (red). Inflammation-induced cytokines up-regulate CD44 expression on β cells. CD44 expression on β cells is associated with increased β cell dysfunction and susceptibility to apoptosis, which could be triggered by the binding of HA fragments to CD44 receptor. However, large HA fragments could interfere with the detrimental effect of LMW-HA on β cells. The β cell dysfunction and susceptibility to apoptosis is indicated by increased iNOS induction and subsequent NO production, increased caspase-3 activity (Western blot, not shown), reduced glucose-stimulated insulin secretion, and reduced insulin content. As an outcome of β cell demise, hyperglycemia is detected, implying the development of T1D. Broken arrows and question marks represent pathways and factors that are yet to be established.