CD14 signaling restrains chronic inflammation through induction of p38-MAPK/SOCS-dependent tolerance.
CD14 signaling restrains chronic inflammation through induction of p38-MAPK/SOCS-dependent tolerance.
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DOI：
10.1371/journal.ppat.1000687
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发表时间：
2009-12
期刊：
影响因子：
6.7
通讯作者：
Sellati TJ
中科院分区：
文献类型：
--
作者：
Sahay B;Patsey RL;Eggers CH;Salazar JC;Radolf JD;Sellati TJ
目前的观点强调CD14在促进某些tlr对微生物的识别以启动促炎信号事件中的首要作用，以及p38-MAPK在增强这种反应中的重要性。本文对这一范式提出了挑战，证明对活体伯氏疏螺旋体的识别不仅在缺乏CD14的情况下引发炎症反应，而且在一定程度上是PI3K/AKT/p38-MAPK信号通路改变和TLR2负调控受损的结果。CD14缺乏导致PI3K在脂筏上的定位增加，AKT的过度磷酸化，p38的激活降低。这种异常信号导致SOCS1、SOCS3和CIS的负调控减弱，从而影响巨噬细胞对伯氏疏螺旋体的耐受性诱导，并产生更严重和持续的炎症反应。重要的是，这些改变的信号事件和观察到的更高的细胞因子产生可以通过shRNA和cd14表达巨噬细胞中p38活性的药理抑制来模拟。这种CD14/p38- mapk依赖性免疫调节的扰动可能是感染性慢性炎症综合征发展的基础。巨噬细胞表达CD14，它与toll样受体2/1结合，识别细菌脂蛋白，如莱姆病病原体伯氏疏螺旋体的脂蛋白。体外证据表明，阻断CD14对细菌成分的识别可以消除先天宿主细胞的炎症反应。同样，阻断下游p38激酶活性会抑制细胞对这些相同微生物刺激的反应。这项工作支持了两种公认的范式，即CD14在促进TLR识别微生物以启动促炎信号事件中的首要作用，以及p38在增强此类反应中的重要性。然而，与这些范例相反，我们先前使用莱姆病小鼠模型的研究表明，CD14缺乏、细菌负担增加和更严重和持续的疾病之间存在关联。在此，我们为这种意想不到的宿主免疫反应提供了一个机制解释，暗示炎症信号通路的负面调节受损是一个潜在的原因。由于负面调节受损，宿主对持续暴露于细菌变得“不耐受”，因此对细菌的存在产生了永久的炎症反应。这些发现提出了一个有趣的问题，即感染严重程度和临床病程的个体差异是否反映了患者先天免疫系统对耐受性的易感性。
Current thinking emphasizes the primacy of CD14 in facilitating recognition of microbes by certain TLRs to initiate pro-inflammatory signaling events and the importance of p38-MAPK in augmenting such responses. Herein, this paradigm is challenged by demonstrating that recognition of live Borrelia burgdorferi not only triggers an inflammatory response in the absence of CD14, but one that is, in part, a consequence of altered PI3K/AKT/p38-MAPK signaling and impaired negative regulation of TLR2. CD14 deficiency results in increased localization of PI3K to lipid rafts, hyperphosphorylation of AKT, and reduced activation of p38. Such aberrant signaling leads to decreased negative regulation by SOCS1, SOCS3, and CIS, thereby compromising the induction of tolerance in macrophages and engendering more severe and persistent inflammatory responses to B. burgdorferi. Importantly, these altered signaling events and the higher cytokine production observed can be mimicked through shRNA and pharmacological inhibition of p38 activity in CD14-expressing macrophages. Perturbation of this CD14/p38-MAPK-dependent immune regulation may underlie development of infectious chronic inflammatory syndromes. Macrophages express CD14 which partners with Toll-like receptor 2/1 to recognize bacterial lipoproteins such as those of Borrelia burgdorferi, the causative agent of Lyme disease. In vitro evidence demonstrates that blocking CD14 recognition of bacterial components ablates innate host cell inflammatory responses. Similarly, blocking downstream p38 kinase activity dampens the cellular response to these same microbial stimuli. This body of work underpins two well-established paradigms which cite the primacy of CD14 in facilitating TLR recognition of microbes to initiate proinflammatory signaling events and the importance of p38 in augmenting such responses. However, contrary to these paradigms, our prior study using a mouse model of Lyme disease demonstrated an association between CD14 deficiency, increased bacterial burden, and more severe and persistent disease. Herein, we provide a mechanistic explanation for this unanticipated host immune response implicating impaired negative regulation of inflammatory signaling pathways as an underlying cause. Consequent to impaired negative regulation the host becomes “intolerant” of continued exposure to bacteria and thus mounts a perpetual inflammatory response to their presence. An intriguing question raised by these findings is whether individual differences in the severity and clinical course of infection might reflect the susceptibility of the patient's innate immune system to tolerization.
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