Investigating how intestinal innate immunity confers neuroprotection using C. elegans

线粒体动态平衡是维持神经元健康和功能所必需的，其 调节失调在使特定神经系统变得脆弱方面起着突出的作用。最近 我们发现p38丝裂原活化蛋白激酶(MAPK； 哺乳动物p38α同源基因)和CREB样转录因子atf-7介导的先天 线虫肠道免疫途径对其神经元的保护作用 由线粒体功能障碍引起。P38MAPK/ATF-7的神经保护作用 肠道中激活的免疫力是通过增强线粒体吞噬作用而发生的，并且 仅肠道细胞中p38MAPK/ATF-7的活性就足以降低线粒体的数量， 不仅在肠道细胞中，在神经元中也是如此。此外，我们实验室获得的初步数据 表明在线虫中，与疾病相关的错误折叠蛋白的外周增加可以 扰乱先天免疫信号通路。因此，我们的中心假设是 衰老和蛋白毒性导致的免疫系统失调可以扰乱 启动或加重神经退行性变的神经元中的线粒体稳态。 该研究的目的是确定p38MAPK/ATF-7如何介导 线虫肠道内激活的先天免疫途径影响线粒体内环境平衡 在神经元中。为此，我们将： 目的1：研究先天免疫反应在神经元维持中的作用 复杂的i功能障碍。 目的2：确定肠道中影响神经元健康的免疫介质。 目的3：研究外周蛋白毒性抗原在破坏免疫信号中的作用。 导致功能障碍的神经元线粒体堆积。 我们的初步数据显示，先天免疫反应调节线粒体 动态平衡以细胞非自主的方式，反过来又可以被特异性地抑制 外周蛋白毒素抗原。因此，这些研究提供了一种新的可能性 免疫衰老是导致功能障碍的线粒体积累的原因，并且 可以为蛋白质毒性在线粒体调节中的作用提供新的见解 动态平衡。

Mitochondrial homeostasis is required to maintain neuronal health and function, and its dysregulation plays prominent roles in rendering specific neural systems vulnerable. Recently we have found that the activation of the p38 mitogen-activated protein kinase (MAPK; the mammalian p38α ortholog) and the CREB like transcription factor ATF-7-mediated innate immune pathway in the intestine of C. elegans can protect its neurons from degeneration induced by mitochondrial dysfunction. The neuroprotective effects of p38MAPK/ATF-7 immunity activated in the gut occurs through the enhancement of mitophagy, and p38MAPK/ATF-7 activity in intestinal cells alone is sufficient to lower mitochondrial numbers, not only in intestinal cells, but also in neurons. Moreover, preliminary data obtained in our lab show that in C. elegans the peripheral increase in disease-related misfolded proteins can disrupt innate immune signaling pathways. Our central hypothesis, therefore, is that aging- and proteotoxicity-induced dysregulation of the immune system can disrupt mitochondrial homeostasis in neurons initiating or aggravating neurodegeneration. The objective of the proposed research is to determine how the p38MAPK/ATF-7-mediated innate immune pathway activated in the gut in C. elegans affects mitochondrial homeostasis in neurons. To do this, we will: Aim 1: Examine the role of the innate immune response in the maintenance of neurons upon Complex I dysfunction. Aim 2: Identify the immune mediators in the gut that affect neuronal health. Aim 3: Examine the role of peripheral proteotoxic antigens in disrupting immune signaling, leading to the accumulation of dysfunctional neuronal mitochondria. Our preliminary data show that the innate immune response modulates mitochondrial homeostasis in a cell non-autonomous manner, and is in turn can be inhibited by specific peripheral proteotoxic antigens. These studies therefore offer the novel possibility that immunosenescence is responsible for the accumulation of dysfunctional mitochondria, and could offer new insights into the role of proteotoxicity in the modulation of mitochondrial homeostasis.