12-Lipoxygenase Governs the Innate Immune Pathogenesis of Islet Inflammation and Autoimmune Diabetes
Macrophages and related myeloid cells are innate immune cells that participate in the early islet inflammation of type 1 diabetes (T1D). The enzyme 12-lipoxygenase (12-LOX) catalyzes the formation of proinflammatory eicosanoids, but its role and mechanisms in myeloid cells in the pathogenesis of islet inflammation have not been elucidated. Leveraging a model of islet inflammation in zebrafish, we show here that macrophages contribute significantly to the loss of β cells and the subsequent development of hyperglycemia. The depletion or inhibition of 12-LOX in this model resulted in reduced macrophage infiltration into islets and the preservation of β cell mass. In NOD mice, the deletion of the gene encoding 12-LOX in the myeloid lineage resulted in reduced insulitis with reductions in proinflammatory macrophages, a suppressed T cell response, preserved β cell mass, and almost complete protection from the development of T1D. 12-LOX depletion caused a defect in myeloid cell migration, a function required for immune surveillance and tissue injury responses. This effect on migration resulted from the loss of the chemokine receptor CXCR3. Transgenic expression of the gene encoding CXCR3 rescued the migratory defect in zebrafish 12-LOX morphants. Taken together, our results reveal a formative role for innate immune cells in the early pathogenesis of T1D and identify 12-LOX as an enzyme required to promote their prodiabetogenic phenotype in the context of autoimmunity.
Kulkarni, A., Pineros, A. R., Walsh, M. A., Casimiro, I., Ibrahim, S., Hernandez-Perez, M., Orr, K. S., Glenn, L., Nadler, J. L., Morris, M. A., Tersey, S. A., Mirmira, R. G., & Anderson, R. M. (2021). 12-Lipoxygenase Governs the Innate Immune Pathogenesis of Islet Inflammation and Autoimmune Diabetes. JCI Insight, 6 (14), 147812-147812. https://doi.org/10.1172/jci.insight.147812