The molecular basis of NOD2 susceptibility mutations in Crohn's disease.
The molecular basis of NOD2 susceptibility mutations in Crohn's disease.
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NOD2是NLR家族中的一员，当接触到来自细菌成分的配体时，NLR家族会启动炎症反应，这些配体可以进入细胞内环境。因此，编码NOD2(CARD15)的基因中导致NOD2功能受损的基因多态性是克罗恩病的易感因素，这是一种以对正常细菌菌群过度炎症反应为特征的疾病，这在某种程度上是矛盾的。在我们实验室进行的一系列研究中，为了更好地确定NOD2的功能并解决这一悖论，我们首先表明，由其配体--胞壁二肽(MDP)激活的NOD2通常下调对TLR刺激的反应，因此缺乏NOD2的细胞对这种刺激的反应增加。这与这样一个事实相吻合，即携带NOD2转基因的小鼠，因此具有增强NOD2功能的细胞对TLR刺激的反应降低，并且对实验性结肠炎诱导具有抵抗力。在分析这些负面影响的进一步研究中，我们发现，用NOD2配体预刺激细胞使其对TLR刺激没有反应，因为这种预刺激导致了IRF4的形成，IRF4是TLR诱导的炎症通路的抑制剂。此外，给正常小鼠注射MDP可诱导IRF4并预防实验性结肠炎。这些研究有力地表明，NOD2基因多态性与克罗恩病有关，因为它们导致正常肠道对TLR反应的负调节减少，从而导致对正常菌群的病理性反应增加。给予MDP预防实验性结肠炎的发现为这种治疗可能平息无NOD2异常患者克罗恩病复发的可能性打开了大门。
Nod2 is a member of the NLR family of proteins that initiate inflammatory responses when exposed to ligands derived from bacterial components that gain access to the intra-cellular milieu. It is thus somewhat paradoxical that polymorphisms in the gene that encode NOD2 (CARD15) that lead to impaired NOD2 function, are susceptibility factors in Crohn's disease, a condition marked by excessive inflammatory responses to normal bacterial flora. In a series of studies conducted in our laboratory to better define NOD2 function and to resolve this paradox we showed first that NOD2 activation by its ligand, muramyl dipeptide (MDP), ordinarily down-regulates responses to TLR stimulation and thus cells lacking NOD2 mount increased responses to such stimulation. This fits with the fact that mice bearing a NOD2 transgene and thus having cells with increased NOD2 function display decreased responses to TLR stimulation and are resistant to experimental colitis induction. In further studies to analyze these negative effecrts we showed that pre-stimulation of cells with NOD2 ligand renders them unresponsive to TLR stimulation because such pre-stimulation results in the elaboration of IRF4, an inhibitor of TLR-induced inflammatory pathways. Furthermore, administration of MDP to normal mice induces IRF4 and prevents experimental colitis. These studies strongly suggest that NOD2 polymorphisms are associated with Crohn's disease because they lead to a decrease in the negative regulation of TLR responses occuring in the normal gut and thus a pathologic increase in responses to the normal flora. The finding that MDP administration prevents experimental colitis opens the door to the possibility that such treatment might quell Crohn's disease relapses in patients without NOD2 abnormalities.
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