RESUMO

Introduction: We reported that Ca2+-independent phospholipase A2ß (iPLA2ß)-derived lipids (iDLs) contribute to type 1 diabetes (T1D) onset. As CD4+ and CD8+ T cells are critical in promoting ß-cell death, we tested the hypothesis that iDL signaling from these cells participates in T1D development. Methods: CD4+ and CD8+ T cells from wild-type non-obese diabetic (NOD) and NOD.iPLA2ß+/- (NOD.HET) mice were administered in different combinations to immunodeficient NOD.scid. Results: In mice receiving only NOD T cells, T1D onset was rapid (5 weeks), incidence 100% by 20 weeks, and islets absent. In contrast, onset was delayed 1 week and incidence reduced 40%-50% in mice receiving combinations that included NOD.HET T cells. Consistently, islets from these non-diabetic mice were devoid of infiltrate and contained insulin-positive ß-cells. Reduced iPLA2ß led to decreased production of proinflammatory lipids from CD4+ T cells including prostaglandins and dihydroxyeicosatrienoic acids (DHETs), products of soluble epoxide hydrolase (sEH), and inhibition of their signaling decreased (by 82%) IFNγ+CD4+ cells abundance. However, only DHETs production was reduced from CD8+ T cells and was accompanied by decreases in sEH and granzyme B. Discussion: These findings suggest that differential select iDL signaling in CD4+ and CD8+ T cells contributes to T1D development, and that therapeutics targeting such signaling might be considered to counter T1D.

Assuntos

Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , Diabetes Mellitus Tipo 1 , Camundongos Endogâmicos NOD , Transdução de Sinais , Animais , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Camundongos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/imunologia , Fosfolipases A2 do Grupo VI/metabolismo , Fosfolipases A2 do Grupo VI/genética , Metabolismo dos Lipídeos , Camundongos SCID , Feminino

RESUMO

Type 1 diabetes (T1D) is a consequence of autoimmune destruction of ß-cells and macrophages (MΦ) have a central role in initiating processes that lead to ß-cell demise. We reported that Ca2+-independent phospholipase A2ß (iPLA2ß)-derived lipid (iDL) signaling contributes to ß-cell death. As MΦ express iPLA2ß, we assessed its role in T1D development. We find that selective reduction of myeloid-iPLA2ß in spontaneously diabetes-prone nonobese diabetic (NOD) mice (a) deceases proinflammatory eicosanoid production by MΦ, (b) favors anti-inflammatory (M2-like) MΦ 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 MΦ polarization and adoptive transfer of M2-like MΦ reduces NOD T1D incidence, suggesting a mechanism by which iDLs impact T1D development. These findings identify MΦ-iPLA2ß as a critical contributor to TID development and potential target to counter T1D onset.