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.
A.Almutairi: None. T.White: None. D.Stephenson: None. Y.Gai: None. E.Ubil: None. C.Chalfant: None. S.Ramanadham: None.
NIH/NIAID R21 (AI 146743) NIH/NIDDK (R01DK110292) Cell, Developmental, & Integrative Biology (CDIB) , the University of Alabama at BirminghamUAB Comprehensive Diabetes CenterKing Saud bin Abdulaziz University for Health Sciences/ Saudi Arabian Cultural Mission