76-OR: Macrophage-Derived Proinflammatory Lipids Play a Role in the Development of Type 1 Diabetes

Type 1 diabetes (T1D) is a consequence of autoimmune-mediated destruction of pancreatic β-cells, but the leading causes for this process remain elusive. We revealed that Ca²⁺-independent phospholipase A₂β (iPLA₂β) , which hydrolyzes membrane phospholipids at the sn-2 position to generate bioactive lipids, modulates polarization of macrophages (MΦ) . Several of the iPLA₂β-derived lipid signals (iDLs) are proinflammatory and can initiate immune cell infiltration and β-cell damage. Recently, we showed that production of MΦ- proinflammatory lipids (i.e., PGs, DHETs, LTB₄) from spontaneous-T1D prone nonobese diabetic mice (NOD) is high during the pre-diabetic phase. Herein, we examined the impact of bone marrow-derived macrophages (BMD-MΦ) -iDLs on T1D development by generating NOD mice with a conditional reduction in MΦ-iPLA₂β (NOD.cMΦ iPLA₂𝛽;^-/- and NOD.cMΦ iPLA₂𝛽;^+/-) . Our findings reveal that (1) BMD-MΦ from NOD.cMΦiPLA₂𝛽;^-/- or NOD.cMΦiPLA₂𝛽;^+/- are skewed towards an M2 (anti-inflammatory) phenotype, in comparison with NOD BMD-MΦ (2) production of proinflammatory lipids (PGs, DHETs, and TXB₂) is significantly decreased in BMD-MΦ from NOD.cMΦiPLA₂𝛽;^-/- and NOD.cMΦiPLA₂𝛽;^+/- (3) selective inhibition of PGE₂ or DHETs signaling inhibits NOD BMD-MΦ polarization towards a proinflammatory phenotype M1 (4) selective decrease of iPLA₂β in MΦ significantly reduces leukocytes infiltration into the pancreas of NOD mice (5) pancreata from NOD.cMΦiPLA₂𝛽;^-/- and NOD.cMΦiPLA₂𝛽;^+/- mice have significantly higher M2 macrophages and less activated T cells (6) importantly, selective decrease of iPLA₂β in MΦ (NOD.cMΦiPLA₂𝛽;^-/- and NOD.cMΦiPLA₂𝛽;^+/-) significantly reduces T1D incidence in NOD mice. The overall reduced macrophages-proinflammatory lipids is associated with increased M2 macrophages and less T1D diabetes pathogenesis in selective decrease of MΦ-iPLA₂β NOD mice. And inhibition of selective macrophages-derived iDLs production can be targeted to counter T1D.