MAPK phosphatase-1 is required for regulatory natural autoantibody-mediated inhibition of TLR responses
MAPK phosphatase-1 is required for regulatory natural autoantibody-mediated inhibition of TLR responses
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DOI：
10.1073/pnas.1211868109
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发表时间：
2012-11-27
影响因子：
11.1
通讯作者：
Silverman, Gregg J.
中科院分区：
文献类型：
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作者：
Groenwall, Caroline;Chen, Yifang;Silverman, Gregg J.
自然产生的IgM抗体，识别凋亡细胞（AC）膜上的新决定簇，从出生时就存在，并可通过AC激发进一步诱导。这种天然产生的IgM抗体可以抑制对纯化的Toll样受体（TLR）激动剂的促炎反应，并阻断IgG免疫复合物诱导的体外和体内病原性反应的诱导。为了研究负责任的机制，我们研究了IgM抗AC抗体对由一系列不同TLR介导的骨髓来源的树突状细胞中的反应的调节作用，发现添加IgM抗AC抑制了主要MAPK的激活：ERK 1/2，JNK，特别是p38。这取决于C1 q或甘露糖结合凝集素的募集，这两者都是标记AC用于先天免疫识别的早期补体因子。引人注目的是，MAPK抑制TLR激动剂和狼疮IgG自身抗体-染色质免疫复合物的反应被发现与MAPK磷酸酶-1的诱导和核定位相关，并且对MAPK磷酸酶-1具有绝对的要求，MAPK磷酸酶-1是已知介导糖皮质激素抑制免疫反应的因子。进一步的实验表明，血清中的天然IgM抗体表现出相同的抑制特性。这些研究阐明了一种新的稳态途径，通过该途径，作为适应性免疫系统产物的天然抗体可以通过募集和协调先天免疫系统的原始调节途径来直接钝化炎症反应。
Naturally arising IgM antibodies, which recognize neo-determinants on apoptotic cell (AC) membranes, are present from birth and can be further induced by AC challenge. Such naturally arising IgM antibodies can suppress proinflammatory responses to purified agonists for Toll-like receptors (TLRs), as well as block the induction of IgG immune complex-induced in vitro and in vivo pathogenic responses. To investigate the responsible mechanisms, we studied the regulatory effects of IgM anti-AC antibody on responses in bone marrow-derived dendritic cells mediated by a range of different TLRs and found that addition of IgM anti-AC inhibited the activation of the primary MAPKs: ERK1/2, JNK, and particularly p38. This was dependent on the recruitment of either C1q or mannose-binding lectin, which are both early complement factors that tag ACs for innate immune recognition. Strikingly, MAPK inhibition of responses to TLR agonists, and to lupus IgG autoantibody-chromatin immune complexes, was found to correlate with, and had an absolute requirement for, the induction and nuclear localization of MAPK phosphatase-1, a factor known to mediate glucocorticoid suppression of immune responses. Further experiments showed that natural IgM antibodies in serum exhibited the same inhibitory properties. These studies elucidate a novel homeostatic pathway by which natural antibodies, which are products of the adaptive immune system, can directly blunt inflammatory responses by recruitment and coordination of a primitive regulatory pathway of the innate immune system.