The MAPK-Activated Kinase MK2 Attenuates Dendritic Cell–Mediated Th1 Differentiation and Autoimmune Encephalomyelitis
The MAPK-Activated Kinase MK2 Attenuates Dendritic Cell–Mediated Th1 Differentiation and Autoimmune Encephalomyelitis
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DOI：
10.4049/jimmunol.1401663
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发表时间：
2015-07
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通讯作者：
K. Soukup;A. Halfmann;M. Le Bras;E. Şahin;S. Vittori;Fiona Poyer;C. Schuh;R. Luger;B. Niederreiter;T. Haider;D. Stoiber;S. Blüml;G. Schabbauer;A. Kotlyarov;M. Gaestel;T. Felzmann;A. Dohnal
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作者：
K. Soukup;A. Halfmann;M. Le Bras;E. Şahin;S. Vittori;Fiona Poyer;C. Schuh;R. Luger;B. Niederreiter;T. Haider;D. Stoiber;S. Blüml;G. Schabbauer;A. Kotlyarov;M. Gaestel;T. Felzmann;A. Dohnal
MAPK 激活的蛋白激酶 (MK)-2（p38 MAPK 的底物）可促进树突状细胞 (DC) 介导的 TLR 介导的炎症。在这项研究中，我们展示了 MK2 的相反作用，它通过调节 p38、ERK1/2-MAPK 和 STAT3 信号传导来巩固 DC 中的免疫调节功能。在初级 TLR/p38 信号传导过程中，MK2 介导 p38 激活的抑制并正向交叉调节 ERK1/2 活性，导致 IL-12 和 IL-1α/β 分泌减少。因此，MK2 损害 DC 中的次级自分泌 IL-1α 信号传导，从而进一步降低 IL-1α/p38，但增加抗炎 IL-10/STAT3 信号传导途径。因此，阻断 MK2 活性使人和鼠 DC 能够在体外通过促进 IL-1α 介导的 Th1 效应器功能来增强促炎效应器机制。此外，MK2 缺陷的 DC 会在体内触发 Th1 分化和 Ag 特异性细胞毒性。最后，在 MK2 抑制剂存在下用 LPS 免疫的野生型小鼠在其淋巴结中大量积聚 Th1 细胞。这些观察结果与 DC 特异性 MK2 敲除小鼠与野生型同窝小鼠相比，在诱导实验性自身免疫性脑炎后出现严重的临床病程相关。我们的数据表明，MK2 具有深远的抗炎作用，可防止 DC 延长过度的 Th1 效应 T 细胞功能和自身免疫。
Dendritic cell (DC)–mediated inflammation induced via TLRs is promoted by MAPK-activated protein kinase (MK)-2, a substrate of p38 MAPK. In this study we show an opposing role of MK2, by which it consolidates immune regulatory functions in DCs through modulation of p38, ERK1/2-MAPK, and STAT3 signaling. During primary TLR/p38 signaling, MK2 mediates the inhibition of p38 activation and positively cross-regulates ERK1/2 activity, leading to a reduction of IL-12 and IL-1α/β secretion. Consequently, MK2 impairs secondary autocrine IL-1α signaling in DCs, which further decreases the IL-1α/p38 but increases the anti-inflammatory IL-10/STAT3 signaling route. Therefore, the blockade of MK2 activity enables human and murine DCs to strengthen proinflammatory effector mechanisms by promoting IL-1α–mediated Th1 effector functions in vitro. Furthermore, MK2-deficient DCs trigger Th1 differentiation and Ag-specific cytotoxicity in vivo. Finally, wild-type mice immunized with LPS in the presence of an MK2 inhibitor strongly accumulate Th1 cells in their lymph nodes. These observations correlate with a severe clinical course in DC-specific MK2 knockout mice compared with wild-type littermates upon induction of experimental autoimmune encephalitis. Our data suggest that MK2 exerts a profound anti-inflammatory effect that prevents DCs from prolonging excessive Th1 effector T cell functions and autoimmunity.