Platelet-derived β2M regulates monocyte inflammatory responses
Platelet-derived β2M regulates monocyte inflammatory responses
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DOI：
10.1172/jci.insight.122943
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发表时间：
2019-03-07
期刊：
影响因子：
8
通讯作者：
Morrell, Craig N.
中科院分区：
文献类型：
--
作者：
Hilt, Zachary T.;Pariser, Daphne N.;Morrell, Craig N.
β 2微球蛋白（β 2 M）是主要组织相容性I类（MHC I）复合物、血色素沉着因子蛋白（HFE）和新生儿Fc受体（FcRn）的分子伴侣，但β 2 M也可能具有较少了解的分子伴侣独立功能。血浆β 2 M升高在神经认知功能下降中具有直接作用，并且是不良心血管事件的风险因素。β 2 M mRNA以非常高的水平存在于血小板中，并且β 2 M是活化的血小板释放物的一部分。除了其更充分研究的血栓形成功能之外，血小板是重要的免疫调节细胞，其释放炎性分子并有助于白细胞运输、活化和分化。我们现在已经发现，血小板衍生的β 2 M是通过非经典TGF β受体信号传导的单核细胞促炎分化的介体。来自仅在血小板中缺乏β 2 M的小鼠的循环单核细胞（Plt-beta 2 M（-/-））具有更促进修复的单核细胞表型，部分依赖于在缺乏β 2 M的情况下血小板源性TGF β信号传导的增加。使用小鼠心肌梗死（MI）模型，Plt-β 2 M（-/-）小鼠MI后促炎性单核细胞反应有限，相反，与WT小鼠相比，表现出早期修复性单核细胞分化，促纤维化肌成纤维细胞反应和心脏功能快速下降。这些数据表明，一个潜在的新的分子伴侣独立的，单核细胞表型调节功能的血小板β 2 M和血小板衍生的2 M和TGF β在单核细胞分化中有相反的作用，可能是重要的组织损伤反应。
beta-2 Microglobulin (beta 2M) is a molecular chaperone for the major histocompatibility class I (MHC I) complex, hemochromatosis factor protein (HFE), and the neonatal Fc receptor (FcRn), but beta 2M may also have less understood chaperone-independent functions. Elevated plasma beta 2M has a direct role in neurocognitive decline and is a risk factor for adverse cardiovascular events. beta 2M mRNA is present in platelets at very high levels, and beta 2M is part of the activated platelet releasate. In addition to their more well-studied thrombotic functions, platelets are important immune regulatory cells that release inflammatory molecules and contribute to leukocyte trafficking, activation, and differentiation. We have now found that platelet-derived beta 2M is a mediator of monocyte proinflammatory differentiation through noncanonical TGF beta receptor signaling. Circulating monocytes from mice lacking beta 2M only in platelets (Plt-beta 2M(-/-)) had a more proreparative monocyte phenotype, in part dependent on increased platelet-derived TGF beta signaling in the absence of beta 2M. Using a mouse myocardial infarction (MI) model, Plt-beta 2M(-/-) mice had limited post-MI proinflammatory monocyte responses and, instead, demonstrated early proreparative monocyte differentiation, profibrotic myofibroblast responses, and a rapid decline in heart function compared with WT mice. These data demonstrate a potentially novel chaperone-independent, monocyte phenotype-regulatory function for platelet beta 2M and that platelet-derived 2M and TGF beta have opposing roles in monocyte differentiation that may be important in tissue injury responses.