111-OR: Macrophage IPLA2ß-Derived Lipid (iDL) Signaling Promote Type 1 Diabetes Development

Type 1 diabetes (T1D) is a consequence of autoimmune-mediated destruction of pancreatic β-cells, and the leading causes for this process are incompletely understood. Our previous work revealed that Ca²⁺-independent phospholipase A₂β (iPLA₂β), which hydrolyzes membrane phospholipids at the sn-2 position and releases bioactive lipids, modulates polarization of macrophages (MΦ). Several of the iPLA₂β derived lipid signals (iDLs) are proinflammatory, which can initiate immune cell infiltration and β-cell damage. Our recent work suggests that MΦ-derived from spontaneous-T1D prone nonobese diabetic mice (NOD) produce a proinflammatory lipids including (PGE₂, 5-HETEs, 20-HETEs, DHETs, LTB₄) at the early stage of the disease (4 weeks), interestingly, the proinflammatory lipid signature is similar to a high-risk T1D individuals. Here, we examined the effects of MΦ-iPLA₂β iDLs by generating a select conditional decrease in iPLA₂β in NOD MΦ (NOD.cMiPLA₂𝛽;;;;^+/-). We found that (1) that the selective decrease of iPLA₂β in MΦ significantly reduces T1D incidence and immune cell infiltration to the islets in the NOD mice. (2) NOD.cMiPLA₂𝛽;;;;^+/- bone marrow-derived (BMD) MΦ are skewed towards an anti-inflammatory phenotype in comparison to NOD BMD MΦ, favoring an anti-inflammatory phenotype. (4) Selective inhibition of (PGE₂ and DHETs) shifted NOD MΦ towards an anti-inflammatory phenotype. These findings suggest that MΦ-iDLs contribute to T1D development, and inhibition of select iDLs production can be targeted to counter T1D development.