Abstract
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.cMiPLA2 ;;;+/-). 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.cMiPLA2 ;;;+/- 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.
Disclosure
A. Almutairi: None. Y. Gai: None. X. Y. Lei: None. D. Stephenson: None. C. Chalfant: None. S. Ramanadham: None.
Funding
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK110292); National Institute of Allergy and Infectious Diseases (R21AI146743)