The Novel Therapeutic Effect of Phosphoinositide 3-Kinase-γ Inhibitor AS605240 in Autoimmune Diabetes

Abstract

Type 1 diabetes (T1D) remains a major health problem worldwide, with a steadily rising incidence yet no cure. Phosphoinositide 3-kinase-γ (PI3Kγ), a member of a family of lipid kinases expressed primarily in leukocytes, has been the subject of substantial research for its role in inflammatory diseases. However, the role of PI3Kγ inhibition in suppressing autoimmune T1D remains to be explored. We tested the role of the PI3Kγ inhibitor AS605240 in preventing and reversing diabetes in NOD mice and assessed the mechanisms by which this inhibition abrogates T1D. Our data indicate that the PI3Kγ pathway is highly activated in T1D. In NOD mice, we found upregulated expression of phosphorylated Akt (PAkt) in splenocytes. Notably, T regulatory cells (Tregs) showed significantly lower expression of PAkt compared with effector T cells. Inhibition of the PI3Kγ pathway by AS605240 efficiently suppressed effector T cells and induced Treg expansion through the cAMP response element-binding pathway. AS605240 effectively prevented and reversed autoimmune diabetes in NOD mice and suppressed T-cell activation and the production of inflammatory cytokines by autoreactive T cells in vitro and in vivo. These studies demonstrate the key role of the PI3Kγ pathway in determining the balance of Tregs and autoreactive cells regulating autoimmune diabetes.

Mechanisms of development of multimorbidity in the elderly

“…Increased PI3K-AKT-mTOR signalling is also found in autoimmune diabetes. Inhibition of PI3K prevents autoimmunity, suggesting a central role for mTOR signalling in immunosenescence [121] and this may be mediated via inhibition of the transcription factor Foxp3 resulting in reduced Treg function [122].…”

PI3K inhibitors as potential therapeutics for autoimmune disease

“…IC87114 also prevented the in vitro activation of diabetogenic T lymphocytes by NOD B cells. Furthermore, IC87114 delayed the onset, reduced severity and prevented progression of autoimmune diabetes in this mouse model [34]. Thus, for the roles of both Tand B-lymphocytes in T1D, the PI3K pathway is a key driver of lymphocyte activation and expansion, making it an attractive target for therapeutic intervention.…”

T cell metabolism in autoimmune diseases

“…Most likely, a decreased suppressive capacity of Treg cells and an enhanced resistance to suppression of Teff cells seem to be the basis of the loss of self-tolerance observed in T1D [112; 113]. What really is hidden behind the alterations in T cell functions is still a matter of debate, but results from an early study have pointed out a strong activation of Akt in splenocytes from NOD mice, which could be prevented by the use of the PI3K inhibitor AS605240 [114]. The amelioration observed in the clinical signs of diabetes after PI3K inhibition could be a consequence of the increase in Treg expansion as well as Teff suppression, probably due to the activation of cAMP response element-binding protein (CREB), a transcription factor shown to be involved in Foxp3 expression [115].…”