| Autor: |
Almutairi, Abdulaziz, White, Tayleur D., Stephenson, Daniel J., Stephenson, Benjamin D., Gai-Tusing, Ying, Goel, Paran, Phillips, Daniel W., Welner, Robert S., Lei, Xiaoyong, Hammock, Bruce D., Chalfant, Charles E., Ramanadham, Sasanka |
| Předmět: |
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| Zdroj: |
Diabetes; 12/1/2024, Vol. 73 Issue 12, p2022-2033, 12p |
| Abstrakt: |
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. Article Highlights: Macrophages play a central role in type 1 diabetes development. Phospholipases A2 hydrolyze membrane glycerophospholipids to release fatty acids that can be metabolized to proinflammatory lipids, and Ca2+-independent phospholipase A2β participates in β-cell death. This study addressed whether microphage Ca2+-independent phospholipase A2β–derived lipid signaling impacts diabetes development. Reducing microphage Ca2+-independent phospholipase A2β inhibits production of proinflammatory eicosanoids favoring anti-inflammatory M2-like microphage polarization; targeting select Ca2+-independent phospholipase A2β–derived proinflammatory lipids attenuates M1-like microphage polarization. Reducing microphage Ca2+-independent phospholipase A2β acts as a switch to mitigate T-cell inflammatory profile and ameliorates the proinflammatory landscape in the islets. Reduction of myeloid Ca2+-independent phospholipase A2β decreases type 1 diabetes incidence. Microphage Ca2+-independent phospholipase A2β lipid signaling is a candidate therapeutic target to counter type 1 diabetes onset. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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