Immunomodulation by interleukin-33 is protective in stroke through modulation of inflammation
Immunomodulation by interleukin-33 is protective in stroke through modulation of inflammation
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DOI：
10.1016/j.bbi.2015.06.013
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发表时间：
2015-10-01
影响因子：
15.1
通讯作者：
Malm, Tarja
中科院分区：
文献类型：
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作者：
Korhonen, Paula;Kanninen, Katja M.;Malm, Tarja
脑卒中在大脑和外周都会引起大量Th1移位的炎症，从而导致卒中的结局。Th1型反应是神经毒性的，而Th2型反应伴随着抗炎细胞因子的分泌，如白介素4(IL-4)。白介素33(IL-33)是一种细胞因子，可诱导Th2型免疫应答，使巨噬细胞/小胶质细胞极化为M2型，并诱导抗炎细胞因子的产生。我们发现，在人类中风中，抑制性IL-33受体Sst2的血浆水平增加，并与中风预后恶化相关，这表明IL-33驱动的Th2型反应不足。在小鼠中，外周注射IL-33减少了中风引起的细胞死亡，并在损伤后5天提高了对侧前爪的敏感性。接受IL-33治疗的小鼠在脾和大脑皮层缺血周围区域的IL-4水平增加。通过注射IL-4抗体中和IL-4，部分阻止了IL-33介导的保护作用。IL-33治疗还减少了缺血区星形胶质细胞的激活，增加了损伤部位精氨酸酶-1免疫阳性小胶质细胞/巨噬细胞的数量。在人类T细胞中，IL-33处理诱导IL-4的分泌，暴露于IL-33的T细胞的条件培养液减少星形胶质细胞的激活。本研究表明，IL-33通过诱导IL-4分泌对缺血性损伤具有保护作用，可能成为治疗中风的一种新的治疗方法。(C)2015 Elsevier Inc.保留所有权利。
Cerebral stroke induces massive Th1-shifted inflammation both in the brain and the periphery, contributing to the outcome of stroke. A Th1-type response is neurotoxic whereas a Th2-type response is accompanied by secretion of anti-inflammatory cytokines, such as interleukin-4 (IL-4). Interleukin-33 (IL-33) is a cytokine known to induce a shift towards the Th2-type immune response, polarize macrophages/microglia towards the M2-type, and induce production of anti-inflammatory cytokines. We found that the plasma levels of the inhibitory IL-33 receptor, sST2, are increased in human stroke and correlate with a worsened stroke outcome, suggesting an insufficient IL-33-driven Th2-type response. In mouse, peripheral administration of IL-33 reduced stroke-induced cell death and improved the sensitivity of the contralateral front paw at 5 days post injury. The IL-33-treated mice had increased levels of IL-4 in the spleen and in the peri-ischemic area of the cortex. Neutralization of IL-4 by administration of an IL-4 antibody partially prevented the IL-33-mediated protection. IL-33 treatment also reduced astrocytic activation in the peri-ischemic area and increased the number of Arginase-1 immunopositive microglia/macrophages at the lesion site. In human T-cells, IL-33 treatment induced IL-4 secretion, and the conditioned media from IL-33-exposed T-cells reduced astrocytic activation. This study demonstrates that IL-33 is protective against ischemic insult by induction of IL-4 secretion and may represent a novel therapeutic approach for the treatment of stroke. (C) 2015 Elsevier Inc. All rights reserved.