Oligodendrocyte-derived IL-33 functions as a microglial survival factor during neuroinvasive flavivirus infection.
Oligodendrocyte-derived IL-33 functions as a microglial survival factor during neuroinvasive flavivirus infection.
复制标题
少突胶质细胞来源的 IL-33 在神经侵袭性黄病毒感染期间充当小胶质细胞存活因子。
DOI：
10.1101/2023.04.11.536332
复制
发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Oberst,Andrew
中科院分区：
文献类型：
--
作者：
Norris,GeoffreyT;Ames,JoshuaM;Ziegler,StevenF;Oberst,Andrew
为了从感染中恢复，生物体必须平衡对病原体的强大免疫应答与对免疫介导的病理学的耐受性。这种平衡在中枢神经系统中特别重要，其复杂的结构、基本功能和有限的自我更新能力使其容易受到病原体和免疫介导的病理学的影响。在这里，我们确定了alarmin IL-33及其受体ST 2作为宿主存活神经侵袭性黄病毒感染的关键。我们确定少突胶质细胞作为IL-33的关键来源，小胶质细胞作为关键的细胞应答者。值得注意的是，我们发现IL-33/ST 2轴不影响病毒控制或适应性免疫应答;相反，它是促进小胶质细胞活化和存活所必需的。在大脑中不存在完整的IL-33/ST 2信号传导的情况下，神经侵袭性黄病毒感染引发单核细胞衍生的外周免疫细胞的异常募集，增加神经元应激和神经元细胞死亡，这些影响损害了生物体存活。这些发现将IL-33鉴定为CNS对病原体引发的免疫和炎症的耐受性的关键介质。
In order to recover from infection, organisms must balance robust immune responses to pathogens with the tolerance of immune-mediated pathology. This balance is particularly critical within the central nervous system, whose complex architecture, essential function, and limited capacity for self-renewal render it susceptible to both pathogen- and immune-mediated pathology. Here, we identify the alarmin IL-33 and its receptor ST2 as critical for host survival to neuroinvasive flavivirus infection. We identify oligodendrocytes as the critical source of IL-33, and microglia as the key cellular responders. Notably, we find that the IL-33/ST2 axis does not impact viral control or adaptive immune responses; rather, it is required to promote the activation and survival of microglia. In the absence of intact IL-33/ST2 signaling in the brain, neuroinvasive flavivirus infection triggered aberrant recruitment of monocyte-derived peripheral immune cells, increased neuronal stress, and neuronal cell death, effects that compromised organismal survival. These findings identify IL-33 as a critical mediator of CNS tolerance to pathogen-initiated immunity and inflammation.