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Bailixiang tea, an herbal medicine formula, co-suppresses TLR2/MAPK8 and TLR2/NF-κB signaling pathways to protect against LPS-triggered cytokine storm in mice

ABSTRACT: we aimed to explore the molecular mechanism underlying its effects through blood proteomics and transcriptomics analyses. To achieve this, mice were orally administered BLX for 24 h after being treated with 5 mg/kg lipopolysaccharide (LPS). The results demonstrated that BLX effectively down-regulated the overproduction of interleukin 6 (IL-6) and tumor necrosis factor-α (TNF-α) in both the serum and lung and spleen tissues. Furthermore, BLX effectively mitigated the overproduction of monocyte chemoattractant protein-1 (MCP-1) in the serum. Histopathological observations further confirmed the significant protective effect of BLX treatment against LPS-induced lung and spleen damage. Through comprehensive multi-omics analysis, it was revealed that BLX specifically targeted and regulated TLR2/MAPK8 and LR2/NF-κB signaling pathways, which play a crucial role in the production of key cytokines.

ORGANISM(S): Mus Musculus

SUBMITTER: Xianyu Li

PROVIDER: PXD051353 | iProX | Thu Apr 11 00:00:00 BST 2024

REPOSITORIES: iProX

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Bailixiang tea, an herbal medicine formula, co-suppresses TLR2/MAPK8 and TLR2/NF-κB signaling pathways to protect against LPS-triggered cytokine storm in mice.

Zhang Fengrong F Liu Mei M Wang Yun Y Zhao Xiaoang X Zhao Chunhui C Liu Dewen D Li Youming Y Xu Xingyue X Li Xianyu X Yang Hongjun H Tian Jixiang J

Journal of ethnopharmacology 20240910 Pt 1

<h4>Ethnopharmacological relevance</h4>Traditional Chinese medicine (TCM) has shown notable effectiveness and safety in managing illnesses linked to cytokine storm(CS). Bailixiang tea (BLX), an herbal medicine formula, which is a compound Chinese medicine composed of Thymus mongolicus (Ronniger) Ronniger (Bailixiang), Glycyrrhiza uralensis Fisch. (Gancao), Citrus reticulata Blanco (Chenpi), Cyperus rotundus L. (Xiangfu), and Perilla frutescens (L.) Britton (Zisu). The objective of this study was ...[more]

PMID: 39265795

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Project description:Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is an inflammatory process of the lungs characterized by increased permeability of the alveolar-capillary membrane with subsequent interstitial/alveolar edema and diffuse alveolar damage. ALI/ARDS can be the results of either direct or indirect lung injury, with pneumonia being the most common direct pulmonary insult and sepsis the most common extra-pulmonary cause. In this study, we employed the murine lipopolysaccharide (LPS)-induced direct and indirect lung injury model to explore the pathogenic mechanisms of pulmonary and extra-pulmonary ARDS, using an unbiased, discovery and quantitative proteomic approach. A total of 1,017 proteins were both identified and quantified in bronchoalveolar lavage fluid (BALF) from control, intratracheal LPS (I.T. LPS, 0.1 mg/kg) and intraperitoneal LPS (I.P. LPS, 5 mg/kg) treated mice. The two LPS groups shared 13 up-regulated and 22 down-regulated proteins compared to the control group. Among them, molecules related to bronchial and type II alveolar epithelial cell functions including cell adhesion molecule 1 and surfactant protein B were reduced, whereas lactotransferrin and resistin like alpha involved in lung innate immunity were upregulated in both LPS groups. Proteomic profiling also identified significant differences in BALF proteins between I.T. and I.P. LPS groups. Ingenuity pathway analysis revealed that acute-phase response signaling was activated by both I.T. and I.P. LPS, however, the magnitude of activation is much greater in I.T. LPS group compared to I.P. LPS group. Intriguingly, two canonical signaling pathways, liver X receptor/retinoid X receptor activation and the production of nitric oxide and reactive oxygen species in macrophages, were activated by I.T. LPS but suppressed by I.P. LPS. In addition, CXCL15 (also known as lungkine) was also up-regulated by I.T LPS but down-regulated by I.P. LPS. In conclusion, our quantitative discovery-based proteomic approach identified commonalities as well as significant differences in BALF protein expression profiles in LPS-induced direct and indirect lung injury, and importantly, LPS-induced indirect lung injury results in suppression of select components of lung innate immunity, which could contribute to the so-called “immunoparalysis” in sepsis patients.

Project description:Background: Therapeutic options capable of resolving inflammatory lung disease resulting from high-consequence occupational and environmental hazards are lacking. Objective: This study seeks to determine the therapeutic potential of direct lung-delivered interleukin (IL)-10 following repeated high concentration lipopolysaccharide exposures. Methods: C57BL/6 mice were intratracheally instilled with LPS (10μg) and then IL-10 (1μg) or vehicle (saline) control 5-hours later. This LPS exposure and treatment paradigm was then repeated daily for the next 2 days. Serum and lung tissues were collected and assessed for proinflammatory and profibrotic mediators. Lung cell infiltrates were enumerated by flow cytometry. Lung sections were stained for myeloperoxidase (MPO), CCR2, vimentin and post-translational protein citrullination (CIT) and malondialdehyde-acetaldehyde (MAA) modifications. Lung function testing and longitudinal in vivo micro-CT imaging were performed. Whole lungs were profiled using bulk RNA sequencing. Results: Repeated IL-10 therapy significantly (p<0.05) mitigated several LPS-induced adverse effects. IL-10 treatment reduced LPS-induced weight loss and serum pentraxin-2 and IL-6 levels. LPS-induced proinflammatory/profibrotic mediators (i.e., TNF-α, IL-6, CXCL1, CCL2, MMP-8, MMP-9, TIMP-1, fibronectin) were decreased with IL-10 treatment. IL-10 reduced LPS-induced influx of lung neutrophils, CD8+ T cells, NK cells, recruited monocyte-macrophages, and monocytes, as well as tissue expression of CCR2+ monocytes/macrophages, MPO+ neutrophils, vimentin, CIT, and MAA. IL-10 treatment reversed LPS-induced airway hyperresponsiveness. Micro-CT imaging confirmed reduction in LPS-induced lung density by IL-10 treatment. Lung-delivered IL-10 therapy administered after daily repeated endotoxin exposures strikingly reduces lung inflammatory and profibrotic processes and airway dysfunction to hasten lung recovery and resolution. Short-term, lung-localized IL-10 therapy following high-consequence environmental exposure events may represent a novel therapy to prevent chronic lung disease development.

Dataset Information

Bailixiang tea, an herbal medicine formula, co-suppresses TLR2/MAPK8 and TLR2/NF-κB signaling pathways to protect against LPS-triggered cytokine storm in mice

Publications

Bailixiang tea, an herbal medicine formula, co-suppresses TLR2/MAPK8 and TLR2/NF-κB signaling pathways to protect against LPS-triggered cytokine storm in mice.

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