Department of Physiology and Pharmacology, Section for Anesthesiology and Intensive Care Medicine, Karolinska Institutet, Stockholm, Sweden.
Function Perioperative Medicine and Intensive Care, Karolinska University Hospital and Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
Exp Physiol. 2020 Sep;105(9):1634-1647. doi: 10.1113/EP088705. Epub 2020 Jul 24.
What is the central question of this study? Are carotid bodies (CBs) modulated by the damage-associated molecular patterns (DAMPs) and humoral factors of aseptic tissue injury? What are the main findings and their importance? DAMPs (HMGB1, S100 A8/A9) and blood plasma from rats subjected to tibia surgery, a model of aseptic injury, stimulate the release of neurotransmitters (ATP, dopamine) and TNF-α from ex vivo rat CBs. All-thiol HMGB1 mediates upregulation of immune-related biological pathways. These data suggest regulation of CB function by endogenous mediators of innate immunity.
The glomus cells of carotid bodies (CBs) are the primary sensors of arterial partial O and CO tensions and moreover serve as multimodal receptors responding also to other stimuli, such as pathogen-associated molecular patterns (PAMPs) produced by acute infection. Modulation of CB function by excessive amounts of these immunomodulators is suggested to be associated with a detrimental hyperinflammatory state. We have hypothesized that yet another class of immunomodulators, endogenous danger-associated molecular patterns (DAMPs), released upon aseptic tissue injury and recognized by the same pathogen recognition receptors as PAMPs, might modulate the CB activity in a fashion similar to PAMPs. We have tested this hypothesis by exposing rat CBs to various DAMPs, such as HMGB1 (all-thiol and disulfide forms) and S100 A8/A9 in a series of ex vivo experiments that demonstrated the release of dopamine and ATP, neurotransmitters known to mediate CB homeostatic responses. We observed a similar response after incubating CBs with conditioned blood plasma obtained from the rats subjected to tibia surgery, a model of aseptic injury. In addition, we have investigated global gene expression in the rat CB using an RNA sequencing approach. Differential gene expression analysis showed all-thiol HMGB1-driven upregulation of a number of prominent pro-inflammatory markers including Il1α and Il1β. Interestingly, conditioned plasma had a more profound effect on the CB transcriptome resulting in inhibition rather than activation of the immune-related pathways. These data are the first to suggest potential modulation of CB function by endogenous mediators of innate immunity.
本研究的核心问题是什么？是损伤相关分子模式 (DAMPs) 和非感染性组织损伤的体液因子调节颈动脉体 (CB) 吗？主要发现及其重要性是什么？DAMPs（HMGB1、S100A8/A9）和来自胫骨手术大鼠的血液血浆，一种非感染性损伤模型，刺激从体外大鼠 CB 释放神经递质（ATP、多巴胺）和 TNF-α。全硫 HMGB1 介导免疫相关生物途径的上调。这些数据表明，内源性先天免疫介质调节 CB 功能。
颈动脉体 (CB) 的球细胞是动脉部分 O 和 CO 张力的主要传感器，而且作为多模态受体，还对其他刺激作出反应，例如急性感染产生的病原体相关分子模式 (PAMPs)。CB 功能的调节，通过这些免疫调节剂的过量，被认为与有害的过度炎症状态有关。我们假设，另一种免疫调节剂，即无菌组织损伤时释放的内源性危险相关分子模式 (DAMPs)，并被相同的病原体识别受体识别为 PAMPs，可能以类似于 PAMPs 的方式调节 CB 活性。我们通过在一系列体外实验中暴露大鼠 CB 于各种 DAMPs（如 HMGB1（全硫和二硫形式）和 S100A8/A9），来验证这一假设，这些实验证明了多巴胺和 ATP 的释放，已知的神经递质介导 CB 稳态反应。我们在孵育 CB 于来自胫骨手术大鼠的条件血液血浆后观察到类似的反应，胫骨手术是一种无菌损伤模型。此外，我们使用 RNA 测序方法研究了大鼠 CB 的全局基因表达。差异基因表达分析显示，全硫 HMGB1 驱动许多突出的促炎标志物（包括 Il1α 和 Il1β）的上调。有趣的是，条件血浆对 CB 转录组有更深远的影响，导致免疫相关途径的抑制而不是激活。这些数据首次表明，内源性先天免疫介质可能调节 CB 功能。
