<b>Selective Reduction of Ca</b><sup><strong>2+</strong></sup><b>-Independent Phospholipase A</b><sub><strong>2</strong></sub><b>b</b><b> (iPLA</b><sub><strong>2</strong></sub><b>b</b><b>)-Derived Lipid Signaling from Macrophages Mitigates Type 1 Diabetes Development</b>
Authors: Almutairi Abdulaziz , D. White Tayleur , J. Stephenson Daniel , D. Stephenson Benjamin , Gai-Tusing Ying , Goel Paran , W. Phillips Daniel , S. Welner Robert , Lei Xiaoyong , D. Hammock Bruce , E. Chalfant Charles , Ramanadham Sasanka 
Published: September 2024

<p dir="ltr"><b>Abstract</b></p><p dir="ltr">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 Ca<sup>2+</sup>-independent phospholipase A<sub>2</sub>b (iPLA<sub>2</sub>b)-derived lipid (iDL) signaling contributes to b-cell death. As MF express <a href="" target="_blank">iPLA<sub>2</sub></a>b, we assessed its role in T1D development. We find that selective reduction of myeloid-iPLA<sub>2</sub>b 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<sup>+</sup> and CD8<sup>+</sup> 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-iPLA<sub>2</sub>b as a critical contributor to TID development and potential target to counter T1D onset.</p><p><br></p><p dir="ltr"><b>Article Highlights</b></p><p dir="ltr"><br><b>a. Why did we undertake this study?</b></p><p dir="ltr">· Macrophages (MF) play a central role in T1D development.</p><p dir="ltr">· Phospholipases A<sub>2</sub> (PLA<sub>2</sub>) hydrolyze membrane glycerophospholipids to release fatty acids that can be metabolized to proinflammatory lipids.</p><p dir="ltr">· Ca<sup>2+</sup>-independent PLA<sub>2</sub>b (iPLA<sub>2</sub>b) participates in b-cell death.</p><p dir="ltr"><br><b>b. What is the specific question(s) we wanted to answer?</b></p><p dir="ltr">· Does MF-iPLA<sub>2</sub>b-derived lipid signaling impact diabetes development ?</p><p dir="ltr"><br><b>c. What did we find?</b></p><p><br></p><p dir="ltr">· Reducing MF-iPLA<sub>2</sub>b inhibits production of proinflammatory eicosanoids favoring anti-inflammatory M2-like MF polarization; targeting select iPLA<sub>2</sub>b-derived pro-inflammatory lipids attenuates M1-like MF polarization.</p><p dir="ltr">· Reducing MF-iPLA<sub>2</sub>b acts as a switch to mitigate T-cell inflammatory profile and ameliorate the proinflammatory landscape in the islets.</p><p dir="ltr">· Reduction of myeloid-iPLA<sub>2</sub>b decreases T1D incidence.</p><p dir="ltr"><br><b>d. What are the implications of our findings?</b></p><p><br></p><p dir="ltr">· MF-iPLA<sub>2</sub>b lipid signaling is a candidate therapeutic target to counter T1D onset.</p>