12-Lipoxygenase Governs the Innate Immune Pathogenesis of Islet Inflammation and Autoimmune Diabetes

Abstract

Macrophages and related myeloid cells are innate immune cells that participate in the early islet inflammation of type 1 diabetes (T1D). The inflammatory signals and antigen presentation by these cells may be inducers of the adaptive immune response that is the hallmark of T1D. The enzyme 12-lipoxygenase (12-LOX) catalyzes the formation of pro-inflammatory eicosanoids from membrane-derived phospholipids, but its role and mechanisms in the pathogenesis of islet inflammation have not been elucidated. Leveraging a model of T1D-like islet inflammation in zebrafish, we show here that macrophages contribute significantly to the loss of β-cells and the subsequent development of hyperglycemia. Depletion or inhibition of 12-LOX in this model resulted in significantly reduced macrophage infiltration into islets with preservation of β-cell mass. In mice, we deleted the gene encoding 12-LOX (Alox15) in the myeloid lineage in the non-obese diabetic (NOD) model of T1D. Myeloid cell-specific Alox15 knockout NOD mice demonstrated reduced insulitis and T-cell responses, preserved β cell mass, and almost complete protection from the development of T1D. A critical effect of 12-LOX depletion appeared secondary to a defect in myeloid cell migration, a function required for immune surveillance and tissue injury responses. This effect on migration appeared to be secondary to the loss of the chemokine receptor CXCR3. Transgenic expression of the gene encoding CXCR3 rescued the migrator defect in zebrafish 12-LOX morphants. Taken together, our results reveal a formative role for innate immune myeloid cells in the early pathogenesis of T1D and identify 12-LOX as a necessary enzyme to promote their pro-diabetogenic phenotype in the context of autoimmunity.

Regulation of Tissue Inflammation by 12-Lipoxygenases

“…Macrophages are among the earliest invading cells in T1D [49], and 12-LOX production by these cells is thought to promote a pro-inflammatory phenotype [50]. In recent studies, morpholino-based depletion of alox12 in zebrafish resulted in an impairment in macrophage migration resulting from reductions in chemokine CXCR3 production [51]. Myeloid-specific deletion of Alox15 in NOD mice led to reduced macrophage infiltration into the islet, preserved β-cell mass, and protection from diabetes [51].…”

“…In recent studies, morpholino-based depletion of alox12 in zebrafish resulted in an impairment in macrophage migration resulting from reductions in chemokine CXCR3 production [51]. Myeloid-specific deletion of Alox15 in NOD mice led to reduced macrophage infiltration into the islet, preserved β-cell mass, and protection from diabetes [51]. The reduction in infiltrating T and B cells in this model likely reflects the important role for macrophages as "bridges" that connect β cells to the adaptive immune system, rather than any inherent role for 12-LOXs in adaptive immune cells.…”