32-OR: Reduction of Macrophage-iPLA2ß–Derived Proinflammatory Lipids Inhibit Type 1 Diabetes Development

Type 1 diabetes (T1D) is a consequence of autoimmune-mediated destruction of pancreatic β-cells, but the leading causes for this process remain elusive. Our lab revealed that Ca2+-independent phospholipase A2β (iPLA2β) modulates the polarization of macrophages (MΦ). Recently, we showed that selective iPLA2β-derived lipid signals (iDLs) produced by MΦ from spontaneous-T1D prone mice (NOD) is high during the pre-diabetic phase. Therefore, we examined the impact of bone marrow-derived macrophages (BMD-MΦ)-iDLs on T1D development by generating NOD mice with conditional reduction in MΦ-iPLA2β (NOD. cM Φ iPLA2𝛽;-/- and NOD. cM Φ iPLA2𝛽;+/-). Our data show that BMD-MΦ from NOD. cM Φ iPLA2𝛽;-/- or NOD. cMΦiPLA2𝛽;+/- are skewed towards an M2 anti-inflammatory phenotype, compared with NOD BMD-MΦ. Also, BMD-MΦ from NOD.cMΦiPLA2𝛽;-/- and NOD.cMΦiPLA2𝛽;+/- have significantly less proinflammatory lipids (PGs, DHETs, and TXB2), compared to NOD BMD-MΦ. Moreover, selective inhibition of PGE2 (EP4 antagonist) or DHET (TPPU) signaling inhibits NOD BMD-MΦ polarization towards an M1 proinflammatory phenotype, as reflected by reductions in M1 markers (Arg2, CXCL10, STAT1, and TNFα) and increases in M2 markers (Arg1, RELA, STAT6, and MRC1). Furthermore, pancreata from NOD.cMΦiPLA2𝛽;-/- and NOD.cMΦiPLA2𝛽;+/- have significantly reduced immune cell (CD4, CD8 and, CD19) infiltration and a higher abundance of M2 anti-inflammatory macrophages relative to NOD pancreata. These outcomes were associated with improved glucose tolerance and significant reduction of T1D incidence in the NOD.cMΦiPLA2𝛽;-/- and NOD.cMΦiPLA2𝛽;+/-, as compared with the incidence in the NOD mice. In summary, reduction of select proinflammatory iDLs production by BMD-MΦ favors M2 anti-inflammatory phenotype, reduced T1D pathogenesis, and T1D incidence. We conclude that MΦ-iDLs contribute to T1D onset and that inhibition of selected macrophages-derived iDLs production can be targeted to counter T1D development Disclosure A.Almutairi: None. Y.Gai: None. J.Nadler: None. C.E.Chalfant: None. S.Ramanadham: None.