Macrophage-Regulatory T Cell Interactions Promote Type 2 Immune Homeostasis Through Resistin-Like Molecule α.
Macrophage-Regulatory T Cell Interactions Promote Type 2 Immune Homeostasis Through Resistin-Like Molecule α.
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DOI：
10.3389/fimmu.2021.710406
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发表时间：
2021
影响因子：
7.3
通讯作者：
Nair MG
中科院分区：
文献类型：
--
作者：
Li J;Kim SY;Lainez NM;Coss D;Nair MG
RELMα是一种小的分泌蛋白，由2型细胞因子激活的“M2”巨噬细胞在蠕虫感染和过敏中表达。在稳态和响应2型细胞因子时，RELMα在腹腔巨噬细胞中高表达，但其在浆膜腔中的功能尚不清楚。在本研究中，我们构建了RELMα TdTomato （Td）报告基因敲除（RαTd）小鼠，并研究了RELMα在IL-4复合物（IL-4c）诱导的腹膜炎症中的功能。我们首先验证了RELMαTd/Td转基因小鼠，发现IL-4c注射导致大的巨噬细胞显著扩增，表达Td而不表达RELMα蛋白，而RELMα+/+小鼠表达RELMα而不表达Td。功能上，与RELMα+/+小鼠相比，RELMαTd/Td小鼠IL-4诱导的腹腔巨噬细胞反应和脾肿大增加。基因表达分析表明，与RELMα - Td/Td腹腔巨噬细胞相比，RELMα+/+巨噬细胞具有更强的增殖和活化能力，与T细胞应答、生长因子和细胞因子信号相关的基因增加，而与骨髓细胞分化和维持相关的基因减少。我们采用腹腔巨噬细胞和T细胞共培养的方法验证了r α - Td/Td巨噬细胞驱动异常T细胞活化的假设。与RELMα+/+或RELMαTd/Td巨噬细胞共培养时，CD4+ T细胞效应反应无差异，但RELMαTd/Td巨噬细胞维持FoxP3+调节性T细胞（Treg）增殖的能力受损。与体外实验结果一致，免疫荧光染色显示，与RELMα+/+脾脏相比，RELMα αTd/Td脾脏中FoxP3+细胞明显减少。综上所述，这些研究确定了一种新的RELMα调控途径，通过表达RELMα的巨噬细胞直接维持Treg增殖来限制2型炎症反应。
RELMα is a small, secreted protein expressed by type 2 cytokine-activated “M2” macrophages in helminth infection and allergy. At steady state and in response to type 2 cytokines, RELMα is highly expressed by peritoneal macrophages, however, its function in the serosal cavity is unclear. In this study, we generated RELMα TdTomato (Td) reporter/knockout (RαTd) mice and investigated RELMα function in IL-4 complex (IL-4c)-induced peritoneal inflammation. We first validated the RELMαTd/Td transgenic mice and showed that IL-4c injection led to the significant expansion of large peritoneal macrophages that expressed Td but not RELMα protein, while RELMα+/+ mice expressed RELMα and not Td. Functionally, RELMαTd/Td mice had increased IL-4 induced peritoneal macrophage responses and splenomegaly compared to RELMα+/+ mice. Gene expression analysis indicated that RELMαTd/Td peritoneal macrophages were more proliferative and activated than RELMα+/+ macrophages, with increased genes associated with T cell responses, growth factor and cytokine signaling, but decreased genes associated with differentiation and maintenance of myeloid cells. We tested the hypothesis that RαTd/Td macrophages drive aberrant T cell activation using peritoneal macrophage and T cell co-culture. There were no differences in CD4+ T cell effector responses when co-cultured with RELMα+/+ or RELMαTd/Td macrophages, however, RELMαTd/Td macrophages were impaired in their ability to sustain proliferation of FoxP3+ regulatory T cells (Treg). Supportive of the in vitro results, immunofluorescent staining of the spleens revealed significantly decreased FoxP3+ cells in the RELMαTd/Td spleens compared to RELMα+/+ spleens. Taken together, these studies identify a new RELMα regulatory pathway whereby RELMα-expressing macrophages directly sustain Treg proliferation to limit type 2 inflammatory responses.