Targeting β Cells May Hold Promise for Preventing and Treating T1D

Although the autoimmune response that reduces β cell numbers has often been the focus of research in type 1 diabetes (T1D), findings from a new study suggest proinflammatory signaling in islet β cells may play a significant role in disease progression.

Although the autoimmune response that reduces the β cell population has often been explored in research on causes of type 1 diabetes (T1D), a new study suggests that inflammatory signaling in β cells themselves may promote autoimmunity in T1D.

The current study, published in Cell Reports, used nonobese diabetic (NOD) mouse models of autoimmune diabetes to investigate the role of the enzyme 12/15-lipoxygenase (12/15-LOX), which is encoded in the Alox15 gene and is known to incite inflammation in β cells. In the T1D setting, 12/15-LOX is recognized as a potential regulator of inflammatory macrophages that may initiate innate immune results on β cells.

“The immune system doesn’t just decide one day that it’s going to attack β beta cells,” senior study author Raghavendra Mirmira, MD, PhD, professor of medicine and director of the Diabetes Translational Research Center at the University of Chicago, said in a statement. “Our thinking was that the β cell itself has somehow fundamentally altered itself to invite that immunity.”

Researchers hypothesized that 12/15-LOX in islets might regulate an inflammatory process that facilitates interaction between β cells and immune cells. To test whether 12/15-LOX signaling in the islet has an impact on immune cells, Alox15 was deleted in the β cells of NOD mice before diabetes onset.

At 25 weeks of age, approximately 10% of female mice with Alox15 deletion had diabetes and 80% of the control littermates had diabetes. In males, none of the mice with deleted Alox15 developed diabetes, whereas about 50% of the control littermates did. Additionally, no changes in β cell mass were noted in mice with deleted Alox15. There were also less immune T cells within the islet environment and programmed cell death-ligand 1 (PD-L1) gene expression, which suppresses autoimmunity, was increased in these mice.

“When we got rid of this gene, the β cells no longer signaled to the immune system and the immune onslaught was completely suppressed, even though we didn’t touch the immune system,” Mirmira said. “That tells us that there is a complex dialogue between β cells and immune cells, and if you intervene in that dialogue, you can prevent diabetes."

Researchers also used primary cultured human islets to explore the link between 12/15 LOX signaling and PD-L1 production. In human β cells, the lipoxygenase 12-LOX is functionally similar to 12/15 LOX and is encoded by the Alox12 gene. The small molecule ML355 inhibits Alox12, and when it was introduced in the cultured human islets that had been treated with proinflammatory cytokines to mimic T1D, those islets showed increased PD-L1 levels.

“This study certainly suggests that inhibiting the enzyme in humans can increase levels of PD-L1, which is very promising,” Mirmira said. “With β cell–targeted therapeutics, we believe that as long as the disease hasn’t progressed to the point that there’s massive destruction of β cells, you can catch an individual before that process starts and prevent the disease progression altogether."

Clinical trials to test ML355 could verify the drug’s effectiveness and potentially provide a novel treatment option for patients at a high risk of developing T1D or those who received their diagnosis recently to halt further damage to the pancreas. It is still not clear exactly how 12-LOX signaling regulates PD-L1 production, and the question of whether it is a direct effect of 12-LOX responding to inflammation or a secondary effect within in an integrated stress response is still under speculation.

Reference

Piñeros AR, Kulkarni A, Gao H, et al. Proinflammatory signaling in islet β cells propagates invasion of pathogenic immune cells in autoimmune diabetes. Cell Rep. Published online June 28, 2022. doi:10.1016/j.celrep.2022.111011