Selective Reduction of Ca²⁺-Independent Phospholipase A₂β (iPLA₂β)-Derived Lipid Signaling From Macrophages Mitigates Type 1 Diabetes Development

Type 1 diabetes (T1D) is a consequence of autoimmune destruction of β-cells, and macrophages (MΦs) have a central role in initiating processes that lead to β-cell demise. We reported that Ca²⁺-independent phospholipase A₂β (iPLA₂β)–derived lipid (iDL) signaling contributes to β-cell death. Because MΦs express iPLA₂β, we assessed its role in T1D development. We find that selective reduction of myeloid-iPLA₂β in spontaneously diabetes-prone NOD mice 1) decreases proinflammatory eicosanoid production by MΦs, 2) favors the anti-inflammatory (M2-like) MΦ phenotype, and 3) diminishes activated CD4⁺ and CD8⁺ T-cells phenotype in the pancreatic infiltrate, prior to T1D onset. These outcomes are associated with a significant reduction in T1D. Further, inhibition of select proinflammatory lipid signaling pathways reduces M1-like MΦ polarization and adoptive transfer of M2-like MΦs reduces NOD T1D incidence, suggesting a mechanism by which iDLs impact T1D development. These findings identify MΦ-iPLA₂β as a critical contributor to T1D development and potential target to counter T1D onset.

• Macrophages play a central role in type 1 diabetes development. Phospholipases A₂ hydrolyze membrane glycerophospholipids to release fatty acids that can be metabolized to proinflammatory lipids, and Ca²⁺-independent phospholipase A₂β participates in β-cell death.

• This study addressed whether microphage Ca²⁺-independent phospholipase A₂β–derived lipid signaling impacts diabetes development.

• Reducing microphage Ca²⁺-independent phospholipase A₂β inhibits production of proinflammatory eicosanoids favoring anti-inflammatory M2-like microphage polarization; targeting select Ca²⁺-independent phospholipase A₂β–derived proinflammatory lipids attenuates M1-like microphage polarization.

• Reducing microphage Ca²⁺-independent phospholipase A₂β acts as a switch to mitigate T-cell inflammatory profile and ameliorates the proinflammatory landscape in the islets.

• Reduction of myeloid Ca²⁺-independent phospholipase A₂β decreases type 1 diabetes incidence.

• Microphage Ca²⁺-independent phospholipase A₂β lipid signaling is a candidate therapeutic target to counter type 1 diabetes onset.