12-Lipoxygenase Inhibition Delays Onset of Autoimmune Diabetes in Human Gene Replacement Mice

Authors

Titli Nargis, Department of Medicine, The University of Chicago
Charanya Muralidharan, Department of Medicine, The University of Chicago
Jacob R. Enriquez, Department of Medicine, The University of Chicago
Jiayi E. Wang, Department of Medicine, The University of Chicago
Kerim B. Kaylan, Department of Medicine, The University of Chicago
Advaita Chakraborty, Department of Medicine, The University of Chicago
Sarida Pratuangtham, Department of Medicine, The University of Chicago
Kayla Figatner, Department of Medicine, The University of Chicago
Jennifer B. Nelson, Department of Medicine, The University of Chicago
Sarah C. May, Department of Medicine, The University of Chicago
Jerry L. Nadler, New York Medical College
Matthew B. Boxer, Veralox Therapeutics
David J. Maloney, Veralox Therapeutics
Sarah A. Tersey, Department of Medicine, The University of Chicago
Raghavendra G. Mirmira, Department of Medicine, The University of Chicago

Author Type(s)

Faculty

DOI

10.1172/jci.insight.185299

Journal Title

JCI Insight

Document Type

Article

Publication Date

12-20-2024

Department

Medicine

Disciplines

Medicine and Health Sciences

Abstract

Type 1 diabetes (T1D) is characterized by the autoimmune destruction of insulin-producing β cells and involves an interplay between β cells and cells of the innate and adaptive immune systems. We investigated the therapeutic potential of targeting 12-lipoxygenase (12-LOX), an enzyme implicated in inflammatory pathways in β cells and macrophages, using a mouse model in which the endogenous mouse Alox15 gene is replaced by the human ALOX12 gene. Our finding demonstrated that VLX-1005, a potent 12-LOX inhibitor, effectively delayed the onset of autoimmune diabetes in human gene replacement non-obese diabetic mice. By spatial proteomics analysis, VLX-1005 treatment resulted in marked reductions in infiltrating T and B cells and macrophages, with accompanying increases in immune checkpoint molecule PD-L1, suggesting a shift toward an immunosuppressive microenvironment. RNA sequencing analysis of isolated islets and polarized proinflammatory macrophages revealed significant alteration of cytokine-responsive pathways and a reduction in IFN response after VLX-1005 treatment. Our studies demonstrated that the ALOX12 human replacement gene mouse provides a platform for the preclinical evaluation of LOX inhibitors and supports VLX-1005 as an inhibitor of human 12-LOX that engages the enzymatic target and alters the inflammatory phenotypes of islets and macrophages to promote the delay of autoimmune diabetes.

Recommended Citation

Nargis, T., Muralidharan, C., Enriquez, J., Wang, J., Kaylan, K., Chakraborty, A., Pratuangtham, S., Figatner, K., Nelson, J., May, S., Nadler, J., Boxer, M., Maloney, D., Tersey, S., & Mirmira, R. (2024). 12-Lipoxygenase Inhibition Delays Onset of Autoimmune Diabetes in Human Gene Replacement Mice. JCI Insight, 9 (24). https://doi.org/10.1172/jci.insight.185299