Interleukin-33 prevents the development of autoimmune diabetes in NOD mice
Interleukin-33 prevents the development of autoimmune diabetes in NOD mice
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Interleukin-33 可预防 NOD 小鼠患自身免疫性糖尿病
DOI：
10.1016/j.intimp.2019.02.018
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发表时间：
2019-05-01
影响因子：
5.6
通讯作者：
Zhang, Xiaojian
中科院分区：
文献类型：
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作者：
Lu, Jingli;Liang, Yan;Zhang, Xiaojian
IL-33/ST 2信号对于叉头框P3（Foxp 3）（+）调节（Treg）细胞的产生是重要的，其有助于疾病背景下的免疫稳态。本研究的目的是确定靶向IL-33/ST 2信号是否可以在非肥胖糖尿病（NOD）小鼠中建立免疫耐受并预防1型糖尿病（T1 D）。用IL-33治疗雌性NOD小鼠4周降低了自身免疫性糖尿病的发病率并延迟了其发病，而IL-33并没有逆转新发糖尿病小鼠的血糖浓度和疾病发展。IL-33减少免疫细胞浸润，增加胰岛素阳性胰岛细胞的数量，以及在胰腺中mRNA水平上增加抗凋亡分子Bcl 2和减少促凋亡分子Caspase 3。IL-33可增加胰腺中磷酸化Akt和磷酸化PI 3 K的表达。全身给予IL-33可增加NOD小鼠脾淋巴细胞中CD 4（+）CD 25（+）Foxp（3+）Treg细胞的数量，诱导Treg细胞相关分子ST 2和GATA 3的表达，并在胰腺淋巴结中增加Foxp 3、Ctla 4和Gata 3的mRNA水平。IL-33信号刺激脾中p44/42（Erk）和p38 MAPK以及CD 39的磷酸化的活化。我们的研究结果表明，IL-33可预防糖尿病前期NOD小鼠的疾病发展，并强调IL-33/ST 2是预防T1 D的潜在治疗靶点。
IL-33/ST2 signal is important for the generation of forkhead box P3 (Foxp3)(+) regulatory (Treg) cells, which contribute to immune homeostasis in the context of diseases. The aim of this study was to determine whether targeting IL-33/ST2 signal could establish immunological tolerance and prevent type 1 diabetes (T1D) in non-obese diabetic (NOD) mice. Female NOD mice treated with IL-33 for 4 weeks decreased the incidence and delayed the onset of autoimmune diabetes, whereas IL-33 did not revert blood glucose concentration and disease development in mice with new-onset diabetes. IL-33 reduced immune cell infiltration, increased the number of insulin-positive islet cells, as well as increased antiapoptosis molecule Bcl2 and reduced proapoptosis molecules Caspase3 at mRNA levels in the pancreas. IL-33 increased the expression of phosphorylated-Akt and phosphorylated-PI3K in the pancreas. Systemic administration of IL-33 increased the number of CD4(+)CD25(+)Foxp(3+)Treg cells and induced expression of Treg cell-associated molecules ST2 and GATA3 in splenic lymphocytes, and increased Foxp3, Ctla4, and Gata3 at the -mRNA level in pancreatic lymph nodes of NOD mice. IL-33 signaling stimulated activation of phosphorylation of p44/42 (Erk) and p38 MAPK, as well as CD39 in the spleen. Our results showed that IL-33 prevents disease development in prediabetic NOD mice, and highlight IL-33/ST2 as a potential therapeutic target to prevent T1D.