Hahnefeld Lisa, Kornstädt Lisa, Kratz Daniel, Ferreirós Nerea, Geisslinger Gerd, Pierre Sandra, Scholich Klaus
Institute of Clinical Pharmacology, University Hospital Goethe University Frankfurt, Germany.
Institute of Clinical Pharmacology, University Hospital Goethe University Frankfurt, Germany; Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Project Group Translational Medicine and Pharmacology, Frankfurt, Germany; Fraunhofer Cluster of Excellence for Immune-Mediated Diseases (CIMD), Frankfurt, Germany.
Biochim Biophys Acta Mol Cell Biol Lipids. 2021 Jan;1866(1):158822. doi: 10.1016/j.bbalip.2020.158822. Epub 2020 Oct 1.
Toll-like receptors (TLR) are crucial for recognizing bacterial, viral or fungal pathogens and to orchestrate the appropriate immune response. The widely expressed TLR2 and TLR4 differentially recognize various pathogens to initiate partly overlapping immune cascades. To better understand the physiological consequences of both immune responses, we performed comparative lipidomic analyses of local paw inflammation in mice induced by the TLR2 and TLR4 agonists, zymosan and lipopolysaccharide (LPS), respectively, which are commonly used in models for inflammation and inflammatory pain. Doses for both agonists were chosen to cause mechanical hypersensitivity with identical strength and duration. Lipidomic analysis showed 5 h after LPS or zymosan injection in both models an increase of ether-phosphatidylcholines (PC O) and their corresponding lyso species with additional lipids being increased only in response to LPS. However, zymosan induced stronger immune cell recruitment and edema formation as compared to LPS. Importantly, only in LPS-induced inflammation the lipid profile in the contralateral paw was altered. Fittingly, the plasma level of various cytokines and chemokines, including IL-1β and IL-6, were significantly increased only in LPS-treated mice. Accordingly LPS induced distinct changes in the lipid profiles of ipsilateral and contralateral paws. Here, oxydized fatty acids, phosphatidylcholines and phosphatidylethanolamines were uniquely upregulated on the contralateral side. Thus, both models cause increased levels of PC O and lyso-PC O lipids at the site of inflammation pointing at a common role in inflammation. Also, LPS initiates systemic changes, which can be detected by changes in the lipid profiles.
Toll样受体（TLR）对于识别细菌、病毒或真菌病原体以及协调适当的免疫反应至关重要。广泛表达的TLR2和TLR4以不同方式识别各种病原体，从而启动部分重叠的免疫级联反应。为了更好地理解这两种免疫反应的生理后果，我们分别对由TLR2和TLR4激动剂酵母聚糖和脂多糖（LPS）诱导的小鼠局部爪部炎症进行了比较脂质组学分析，这两种激动剂常用于炎症和炎性疼痛模型。两种激动剂的剂量选择为引起强度和持续时间相同的机械性超敏反应。脂质组学分析显示，在两个模型中，LPS或酵母聚糖注射后5小时，醚磷脂酰胆碱（PC O）及其相应的溶血产物增加，只有LPS刺激后其他脂质才增加。然而，与LPS相比，酵母聚糖诱导更强的免疫细胞募集和水肿形成。重要的是，只有在LPS诱导的炎症中，对侧爪部的脂质谱才发生改变。相应地，包括IL-1β和IL-6在内的各种细胞因子和趋化因子的血浆水平仅在LPS处理的小鼠中显著升高。因此，LPS在同侧和对侧爪部的脂质谱中诱导了明显的变化。在这里，氧化脂肪酸、磷脂酰胆碱和磷脂酰乙醇胺在对侧独特地上调。因此，两种模型在炎症部位均导致PC O和溶血PC O脂质水平升高，表明它们在炎症中起共同作用。此外，LPS引发全身变化，可通过脂质谱的变化检测到。
