Selective Reduction of Ca²⁺-Independent Phospholipase A₂b (iPLA₂b)-Derived Lipid Signaling from Macrophages Mitigates Type 1 Diabetes Development

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.