Disturbances in glucose homeostasis and low-grade chronic inflammation culminate into metabolic syndrome that increase the risk for the development of type 2 diabetes mellitus (T2DM). The recently discovered group 2 innate lymphoid cells (ILC2s) are capable of secreting copious amounts of type 2 cytokines to modulate metabolic homeostasis in adipose tissue. In this study, we have established that expression of Death Receptor 3 (DR3), a member of the TNF superfamily, on visceral adipose tissue (VAT)-derived murine and peripheral blood human ILC2s is inducible by IL-33. We demonstrate that DR3 engages the canonical and/or non-canonical NF-κB pathways, and thus stimulates naïve and co-stimulates IL-33-activated ILC2s. Importantly, DR3 engagement on ILC2s significantly ameliorates glucose tolerance, protects against insulin-resistance onset and remarkably reverses already established insulin-resistance. Taken together, these results convey the potent role of DR3 as an ILC2 regulator and introduce DR3 agonistic treatment as a novel therapeutic avenue for treating T2DM.

葡萄糖稳态紊乱和低度慢性炎症最终会导致代谢综合征，从而增加患 2 型糖尿病 (T2DM) 的风险。最近发现的第 2 组先天淋巴细胞 (ILC2) 能够分泌大量的 2 型细胞因子来调节脂肪组织中的代谢稳态。在这项研究中，我们已经确定死亡受体 3 (DR3) 是 TNF 超家族的成员，在内脏脂肪组织 (VAT) 衍生的小鼠和外周血人 ILC2 上的表达是由 IL-33 诱导的。我们证明 DR3 参与经典和/或非经典 NF-κB 通路，从而刺激幼稚和共同刺激 IL-33 激活的 ILC2。重要的是，ILC2 上的 DR3 参与显着改善了葡萄糖耐量，防止胰岛素抵抗发作并显着逆转已经建立的胰岛素抵抗。总之，这些结果传达了 DR3 作为 ILC2 调节剂的有效作用，并引入了 DR3 激动疗法作为治疗 T2DM 的新治疗途径。