Cell type specific IL-27p28 (IL-30) deletion in mice uncovers an unexpected regulatory function of IL-30 in autoimmune inflammation.
Cell type specific IL-27p28 (IL-30) deletion in mice uncovers an unexpected regulatory function of IL-30 in autoimmune inflammation.
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DOI：
10.1038/s41598-023-27413-w
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发表时间：
2023-02-01
影响因子：
4.6
通讯作者：
中科院分区：
文献类型：
--
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IL-27是一种具有免疫调节功能的IL-12家族细胞因子，能够调节包括自身免疫在内的炎症反应。虽然广泛的研究调查了IL-27介导其功能的主要靶细胞，但IL-27的来源，特别是在组织特异性自身免疫性炎症过程中，还没有正式研究过。IL-27p28亚基又称IL-30，最初被发现是IL-27的特异性亚基，因此被认为是表达IL-27的替代标志物。然而，IL-30可以独立于Ebi3分泌，Ebi3是一个亚基，与IL-30形成生物活性的IL-27。此外，IL-30本身可能起到对抗IL-27的负性调节作用。在这项研究中，我们利用了各种细胞类型特异性的IL-30缺陷小鼠模型，并研究了T细胞介导的自身免疫性神经炎中IL-30的来源。我们发现，IL-30由浸润性和中枢神经系统驻留的APC亚群、浸润性髓系细胞和小胶质细胞表达，是限制炎症的中心。然而，树突状细胞来源的IL-30对于疾病的发展是必不可少的。出乎意料的是，在发生严重EAE的细胞型特异性IL-30缺陷小鼠中，其余野生型APC亚群中IL-30的表达不成比例地增加，这表明内源性IL-30产生的增加可能参与了严重的发病机制。在支持方面，全身应用重组IL-30加重了EAE的严重程度。我们的结果表明，内源性IL-30表达异常可能干扰了IL-27的免疫调节功能，从而促进了体内的脑源性炎症。
IL-27 is an IL-12 family cytokine with immune regulatory properties, capable of modulating inflammatory responses, including autoimmunity. While extensive studies investigated the major target cells of IL-27 mediating its functions, the source of IL-27 especially during tissue specific autoimmune inflammation has not formally been examined. IL-27p28 subunit, also known as IL-30, was initially discovered as an IL-27-specific subunit, and it has thus been deemed as a surrogate marker to denote IL-27 expression. However, IL-30 can be secreted independently of Ebi3, a subunit that forms bioactive IL-27 with IL-30. Moreover, IL-30 itself may act as a negative regulator antagonizing IL-27. In this study, we exploited various cell type specific IL-30-deficient mouse models and examined the source of IL-30 in a T cell mediated autoimmune neuroinflammation. We found that IL-30 expressed by infiltrating and CNS resident APC subsets, infiltrating myeloid cells and microglia, is central in limiting the inflammation. However, dendritic cell-derived IL-30 was dispensable for the disease development. Unexpectedly, in cell type specific IL-30 deficient mice that develop severe EAE, IL-30 expression in the remaining wild-type APC subsets is disproportionately increased, suggesting that increased endogenous IL-30 production may be involved in the severe pathogenesis. In support, systemic recombinant IL-30 administration exacerbates EAE severity. Our results demonstrate that dysregulated endogenous IL-30 expression may interfere with immune regulatory functions of IL-27, promoting encephalitogenic inflammation in vivo.
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