Prevention of Islet Inflammatory Stress with JAK1/JAK2 Inhibitors

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Abstract

Introduction

There is an opportunity to repurpose therapeutics from other diseases to autoimmunity and transplantation, especially when there is evidence for overlapping mechanisms. Inflammation is one of the main causes of islet damage and loss during islet isolation and transplantation, and autoimmune diabetes is associated with a pro-inflammatory environment around pancreatic islets. The JAK-STAT pathway is activated by inflammatory cytokines and is important in T cells and pancreatic beta cells, the target of T cell-mediated destruction. We tested the hypothesis that blocking the response to cytokines that activate the JAK-STAT pathway would prevent islet inflammation, using ruxolitinib, a drug that selectively inhibits JAK1/JAK2.

Materials and Methods

Isolated human or mouse islets were cultured with pro-inflammatory cytokines (IFNγ, TNFα and IL-1β) to induce an inflammatory gene signature, which was measured by quantitative real-time PCR. The JAK1/JAK2 inhibitor ruxolitinib was used to prevent islet inflammation and cell death, measured by flow cytometry.

Results

Ruxolitinib successfully blocked IFNγ-induced phosphorylation of STAT1 and IFNγ-induced MHC class-I upregulation in mouse and human islets. Islet cell death induced by IFNγ, TNFα and IL-1β was completely prevented by JAK inhibitors. Expression of CXCL10, NOS2 and IL6 was upregulated by cytokines, and this was inhibited by ruxolitinib. Ruxolitinib also prevented cytokine-induced LDHA expression and restored PDX1 expression in isolated islets. Mouse islets were protected from CTL-mediated killing in vitro by JAK1/JAK2 inhibitors. Furthermore, NOD mice treated with JAK1/JAK2 inhibitors were protected from autoimmune diabetes, and diabetes was reversed in newly diagnosed NOD mice.

Discussion

The transplantation of islets for the treatment of type 1 diabetes is currently limited by the loss of functional islet mass throughout the procedures of isolation and infusion at least in part due to inflammatory stress. This study investigated the potential for the JAK1/JAK2 inhibitor ruxolitinib to prevent these effects. Our results showing that ruxolitinib can prevent the effects of pro-inflammatory cytokines on islet gene expression and cell death suggest that it is a promising strategy to prevent these effects during islet transplantation.

Conclusion

JAK1/JAK2 inhibitors are clinically approved for other indications including rheumatoid arthritis. Our work provides mechanistic groundwork for repurposing these drugs for islet transplantation.

Conclusion

The National Health and Medical Research Council of Australia GNT1037321.

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