Selective Reduction of Ca2+-Independent Phospholipase A2β (iPLA2β)-Derived Lipid Signaling From Macrophages Mitigates Type 1 Diabetes Development
Year: 2024
Type: article
Abstract: Type 1 diabetes (T1D) is a consequence of autoimmune destruction of β-cells, and macrophages (MΦs) have a central role in initiating processes that lead to β-cell demise. We reported that Ca2+-independent phospholipase A2β (iPLA2β)-derived lipid (iDL) signaling contributes to β-cell death. Because MΦs express iPLA2β, we assessed its role in T1D development. We find that selective reduction of myeloid-iPLA2β in spontaneously diabetes-prone NOD mice 1) decreases proinflammatory eicosanoid production by MΦs, 2) favors the anti-inflammatory (M2-like) MΦ phenotype, and 3) 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 MΦ polarization and adoptive transfer of M2-like MΦs reduces NOD T1D incidence, suggesting a mechanism by which iDLs impact T1D development. These findings identify MΦ-iPLA2β as a critical contributor to T1D development and potential target to counter T1D onset.
Source: Diabetes
DOI: 10.2337/db23-0770
Institutions: King Saud bin Abdulaziz University for Health Sciences, University of Alabama at Birmingham, King Abdullah International Medical Research Center, UAB Medicine, University of Virginia, University of Virginia Medical Center, University of Virginia Cancer Center, University of California, Davis, United States Department of Veterans Affairs, Veterans Health Administration, Hunter Holmes McGuire VA Medical Center
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
Funders: U.S. Department of Veterans Affairs, Eastern Washington University, Cardinal Health, National Institutes of Health, National Heart, Lung, and Blood Institute, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Environmental Health Sciences, JDRF
Awards: G1503134167, iPLA2beta-mediated alternative splicing and beta-cell death in type 1 diabetes, G2366971526, G239213543, G261043369, G2873611288, The role and mechanistic regulation of cPLA2alpha in eicosanoid biosynthesis and wound healing, G4670433464, G6754326463, G7057565231, G7368947, G7684433242, G7715598280, G773047840, G8173979607, G9000073175, G9000103557, G9000117304, G9000162744, G9000169121, G9000200138, G9000258712, Role of bone marrow Tregs in maintaining stromal cell function
OpenAlex ID: W4402581641