Selective Reduction of Ca2+-Independent Phospholipase A2b (iPLA2b)-Derived Lipid Signaling from Macrophages Mitigates Type 1 Diabetes Development
Year: 2024
Type: other
Abstract: Type 1 diabetes (T1D) is a consequence of autoimmune destruction of b-cells and macrophages (MF) have a central role in initiating processes that lead to b-cell demise. We reported that Ca2+-independent phospholipase A2b (iPLA2b)-derived lipid (iDL) signaling contributes to b-cell death. As MF express iPLA2b, we assessed its role in T1D development. We find that selective reduction of myeloid-iPLA2b in spontaneously diabetes-prone non-obese diabetic (NOD) mice (a) deceases proinflammatory eicosanoid production by MF, (b) favors anti-inflammatory (M2-like) MF phenotype, and (c) diminishes activated CD4+ and CD8+ T-cells phenotype in the pancreatic infiltrate, prior to T1D onset. These outcomes are associated with a significant reduction in T1D. Further, inhibition of select proinflammatory lipid signaling pathways reduces M1-like MF polarization and adoptive transfer of M2-like MF reduces NOD T1D incidence, suggesting a mechanism by which iDLs impact T1D development. These findings identify MF-iPLA2b as a critical contributor to TID development and potential target to counter T1D onset. Article Highlights a. Why did we undertake this study? · Macrophages (MF) play a central role in T1D development. · Phospholipases A2 (PLA2) hydrolyze membrane glycerophospholipids to release fatty acids that can be metabolized to proinflammatory lipids. · Ca2+-independent PLA2b (iPLA2b) participates in b-cell death. b. What is the specific question(s) we wanted to answer? · Does MF-iPLA2b-derived lipid signaling impact diabetes development ? c. What did we find? · Reducing MF-iPLA2b inhibits production of proinflammatory eicosanoids favoring anti-inflammatory M2-like MF polarization; targeting select iPLA2b-derived pro-inflammatory lipids attenuates M1-like MF polarization. · Reducing MF-iPLA2b acts as a switch to mitigate T-cell inflammatory profile and ameliorate the proinflammatory landscape in the islets. · Reduction of myeloid-iPLA2b decreases T1D incidence. d. What are the implications of our findings? · MF-iPLA2b lipid signaling is a candidate therapeutic target to counter T1D onset.
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
OpenAlex ID: W4402791523