Advisor(s)
Sasanka Ramanadham
Committee Member(s)
Robert Welner
Sushant Bhatnagar
Charles Chalfant
Bradley K Yoder
Document Type
Dissertation
Date of Award
2023
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
Type 1 Diabetes (T1D) is an autoimmune disease characterized by the destruction of insulin-secreting pancreatic β-cells that leads to hyperglycemia; however, the mechanism of β-cells destruction remains elusive. Ca2+-independent phospholipase A2β (iPLA2β), which hydrolyzes membrane phospholipids at the sn-2 position and releases bioactive lipids, modulates polarization of macrophages (M ). Data from our lab suggests that selective iPLA2β-derived lipid signals (iDLs) (i.e., PGs, HETEs, DHETs, LTB4) produced by M from spontaneous-T1D prone nonobese diabetic mice (NOD) are high during the pre-diabetic phase. However, the impact of macrophage-derived iDLs in T1D remains unclear. Therefore, we generated a NOD mouse model with a conditional reduction in macrophage iPLA2β, cHET, and cKO mice, to examine the roles of macrophage-iDLs on T1D development. We show that reduction of iPLA2β in macrophages can inhibit macrophage proinflammatory polarization (M1) and reduces production of select proinflammatory iDLs (PGs, DHETs, and TXB2) during the disease stage (14 weeks of age). Furthermore, selective inhibition of DHET production or PGE2 signaling diminish NOD macrophage polarization towards an M1 proinflammatory phenotype. We expand on these findings to show how modulation of macrophage-iPLA2β selectively protects from T1D development. We show cHET and cKO mice have conferred significantly reduced pancreatic immune cell infiltration, reduced diabetes incidence and improved glucose homeostasis. Moreover, pancreata of cHET and cKO NOD mice iv exhibited increased anti-inflammatory (M2) macrophage and less TNF+CD4+ and TNF+CD8+ T cells suggesting that reduction of macrophage-iPLA2β can halt an ongoing autoimmune disease process. The conclusions from this work provide a direction for the modulation of macrophage-iPLA2β expression and macrophage-derived iDLs to counter T1D development.
Recommended Citation
Almutairi, Abdulaziz Saad, "Macrophage IPLA2ß-Derived Lipid Signaling Contributes to Type 1 Diabetes Development" (2023). All ETDs from UAB. 447.
https://digitalcommons.library.uab.edu/etd-collection/447
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