Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Journal of Translational Medicine
Published in: Journal of Translational Medicine 1/2024

Open Access 01-12-2024 | Propofol | Research

Propofol improves survival in a murine model of sepsis via inhibiting Rab5a-mediated intracellular trafficking of TLR4

Authors: Bo-Wei Zhou, Wen-Juan Zhang, Fang-Ling Zhang, Xiao Yang, Yu-Qi Ding, Zhi-Wen Yao, Zheng-Zheng Yan, Bing-Cheng Zhao, Xiao-Dong Chen, Cai Li, Ke-Xuan Liu

Published in: Journal of Translational Medicine | Issue 1/2024

Login to get access

Abstract

Background

Propofol is a widely used anesthetic and sedative, which has been reported to exert an anti-inflammatory effect. TLR4 plays a critical role in coordinating the immuno-inflammatory response during sepsis. Whether propofol can act as an immunomodulator through regulating TLR4 is still unclear. Given its potential as a sepsis therapy, we investigated the mechanisms underlying the immunomodulatory activity of propofol.

Methods

The effects of propofol on TLR4 and Rab5a (a master regulator involved in intracellular trafficking of immune factors) were investigated in macrophage (from Rab5a−/− and WT mice) following treatment with lipopolysaccharide (LPS) or cecal ligation and puncture (CLP) in vitro and in vivo, and peripheral blood monocyte from sepsis patients and healthy volunteers.

Results

We showed that propofol reduced membrane TLR4 expression on macrophages in vitro and in vivo. Rab5a participated in TLR4 intracellular trafficking and both Rab5a expression and the interaction between Rab5a and TLR4 were inhibited by propofol. We also showed Rab5a upregulation in peripheral blood monocytes of septic patients, accompanied by increased TLR4 expression on the cell surface. Propofol downregulated the expression of Rab5a and TLR4 in these cells.

Conclusions

We demonstrated that Rab5a regulates intracellular trafficking of TLR4 and that propofol reduces membrane TLR4 expression on macrophages by targeting Rab5a. Our study not only reveals a novel mechanism for the immunomodulatory effect of propofol but also indicates that Rab5a may be a potential therapeutic target against sepsis.
Appendix
Available only for authorised users
Literature
1.
Deng F, Chen Y, Sun QS, Lin ZB, Min Y, Zhao BC, Huang ZB, Liu WF, Li C, Hu JJ, Liu KX. Gut microbiota dysbiosis is associated with sepsis-induced cardiomyopathy in patients: a case-control study. J Med Virol. 2023;95:e28267.PubMedCrossRef
2.
3.
4.
Habre C, Tramer MR, Popping DM, Elia N. Ability of a meta-analysis to prevent redundant research: systematic review of studies on pain from propofol injection. BMJ. 2014;348: g5219.PubMedCrossRef
5.
An K, Shu H, Huang W, Huang X, Xu M, Yang L, Xu K, Wang C. Effects of propofol on pulmonary inflammatory response and dysfunction induced by cardiopulmonary bypass. Anaesthesia. 2008;63:1187–92.PubMedCrossRef
6.
Liu KX, Chen SQ, Huang WQ, Li YS, Irwin MG, Xia Z. Propofol pretreatment reduces ceramide production and attenuates intestinal mucosal apoptosis induced by intestinal ischemia/reperfusion in rats. Anesth Analg. 2008;107:1884–91.PubMedCrossRef
7.
Liu KX, Rinne T, He W, Wang F, Xia Z. Propofol attenuates intestinal mucosa injury induced by intestinal ischemia-reperfusion in the rat. Can J Anaesth. 2007;54:366–74.PubMedCrossRef
8.
Chen X, Wu R, Li L, Zeng Y, Chen J, Wei M, Feng Y, Chen G, Wang Y, Lin L, et al. Pregnancy-induced changes to the gut microbiota drive macrophage pyroptosis and exacerbate septic inflammation. Immunity. 2023;56:336-352.e339.PubMedCrossRef
9.
Patoli D, Mignotte F, Deckert V, Dusuel A, Dumont A, Rieu A, Jalil A, Van Dongen K, Bourgeois T, Gautier T, et al. Inhibition of mitophagy drives macrophage activation and antibacterial defense during sepsis. J Clin Invest. 2020;130:5858–74.PubMedPubMedCentralCrossRef
10.
Ryu JK, Kim SJ, Rah SH, Kang JI, Jung HE, Lee D, Lee HK, Lee JO, Park BS, Yoon TY, Kim HM. Reconstruction of LPS transfer cascade reveals structural determinants within LBP, CD14, and TLR4-MD2 for efficient LPS recognition and transfer. Immunity. 2017;46:38–50.PubMedCrossRef
11.
West AP, Brodsky IE, Rahner C, Woo DK, Erdjument-Bromage H, Tempst P, Walsh MC, Choi Y, Shadel GS, Ghosh S. TLR signalling augments macrophage bactericidal activity through mitochondrial ROS. Nature. 2011;472:476–80.PubMedPubMedCentralCrossRef
12.
Wang D, Lou J, Ouyang C, Chen W, Liu Y, Liu X, Cao X, Wang J, Lu L. Ras-related protein Rab10 facilitates TLR4 signaling by promoting replenishment of TLR4 onto the plasma membrane. Proc Natl Acad Sci USA. 2010;107:13806–11.PubMedPubMedCentralCrossRef
13.
Dai QD, Wu KS, Xu LP, Zhang Y, Lin N, Jiang Y, Shao CY, Su LD. Toll-like receptor 4 deficiency ameliorates propofol-induced impairments of cognitive function and synaptic plasticity in young mice. Mol Neurobiol. 2023;61(1):519–32.PubMedCrossRef
14.
Gao Y, Han T, Han C, Sun H, Yang X, Zhang D, Ni X. Propofol regulates the TLR4/NF-κB pathway through miRNA-155 to protect colorectal cancer intestinal barrier. Inflammation. 2021;44:2078–90.PubMedCrossRef
15.
Langemeyer L, Frohlich F, Ungermann C. Rab GTPase function in endosome and lysosome biogenesis. Trends Cell Biol. 2018;28:957–70.PubMedCrossRef
16.
Gong B, Li Z, Xiao W, Li G, Ding S, Meng A, Jia S. Sec14l3 potentiates VEGFR2 signaling to regulate zebrafish vasculogenesis. Nat Commun. 2019;10:1606.PubMedPubMedCentralCrossRef
17.
Tang J, Zhou B, Scott MJ, Chen L, Lai D, Fan EK, Li Y, Wu Q, Billiar TR, Wilson MA, et al. EGFR signaling augments TLR4 cell surface expression and function in macrophages via regulation of Rab5a activation. Protein Cell. 2020;11:144–9.PubMedCrossRef
18.
Li Z, Scott MJ, Fan EK, Li Y, Liu J, Xiao G, Li S, Billiar TR, Wilson MA, Jiang Y, Fan J. Tissue damage negatively regulates LPS-induced macrophage necroptosis. Cell Death Differ. 2016;23:1428–47.PubMedPubMedCentralCrossRef
19.
20.
21.
Gong S, Yan Z, Liu Z, Niu M, Fang H, Li N, Huang C, Li L, Chen G, Luo H, et al. Intestinal microbiota mediates the susceptibility to polymicrobial sepsis-induced liver injury by granisetron generation in mice. Hepatology. 2019;69:1751–67.PubMedCrossRef
22.
Yeh CH, Cho W, So EC, Chu CC, Lin MC, Wang JJ, Hsing CH. Propofol inhibits lipopolysaccharide-induced lung epithelial cell injury by reducing hypoxia-inducible factor-1alpha expression. Br J Anaesth. 2011;106:590–9.PubMedCrossRef
23.
Mei SH, Haitsma JJ, Dos Santos CC, Deng Y, Lai PF, Slutsky AS, Liles WC, Stewart DJ. Mesenchymal stem cells reduce inflammation while enhancing bacterial clearance and improving survival in sepsis. Am J Respir Crit Care Med. 2010;182:1047–57.PubMedCrossRef
24.
Zhang Y, Zheng D, Zhou T. Androgen deprivation promotes neuroendocrine differentiation and angiogenesis through CREB-EZH2-TSP1 pathway in prostate cancers. Nat Commun. 2018;9:4080.PubMedPubMedCentralCrossRef
25.
Zeng Z, Li Y, Pan Y, Lan X, Song F, Sun J, Zhou K, Liu X, Ren X, Wang F, et al. Cancer-derived exosomal miR-25-3p promotes pre-metastatic niche formation by inducing vascular permeability and angiogenesis. Nat Commun. 2018;9:5395.PubMedPubMedCentralCrossRef
26.
Hou J, Chen Q, Wu X, Zhao D, Reuveni H, Licht T, Xu M, Hu H, Hoeft A, Ben-Sasson SA, et al. S1PR3 signaling drives bacterial killing and is required for survival in bacterial sepsis. Am J Respir Crit Care Med. 2017;196:1559–70.PubMedCrossRef
27.
Hsiao CC, Chen PH, Cheng CI, Tsai MS, Chang CY, Lu SC, Hsieh MC, Lin YC, Lee PH, Kao YH. Toll-like receptor-4 is a target for suppression of proliferation and chemoresistance in HepG2 hepatoblastoma cells. Acta Neuropathol. 2015;368:144–52.
28.
Hughes CD, Choi ML, Ryten M, Hopkins L, Drews A, Botia JA, Iljina M, Rodrigues M, Gagliano SA, Gandhi S, et al. Picomolar concentrations of oligomeric alpha-synuclein sensitizes TLR4 to play an initiating role in Parkinson’s disease pathogenesis. Acta Neuropathol. 2019;137:103–20.PubMedCrossRef
29.
Malinverno C, Corallino S, Giavazzi F, Bergert M, Li Q, Leoni M, Disanza A, Frittoli E, Oldani A, Martini E, et al. Endocytic reawakening of motility in jammed epithelia. Nat Mater. 2017;16:587–96.PubMedPubMedCentralCrossRef
30.
Nguyen MK, Kim CY, Kim JM, Park BO, Lee S, Park H, Heo WD. Optogenetic oligomerization of Rab GTPases regulates intracellular membrane trafficking. Nat Chem Biol. 2016;12:431–6.PubMedCrossRef
31.
He K, Yan X, Li N, Dang S, Xu L, Zhao B, Li Z, Lv Z, Fang X, Zhang Y, Chen YG. Internalization of the TGF-beta type I receptor into caveolin-1 and EEA1 double-positive early endosomes. Cell Res. 2015;25:738–52.PubMedPubMedCentralCrossRef
32.
Fuster JJ. TLR4 in atherogenesis: paying the toll for antimicrobial defense. J Am Coll Cardiol. 2018;71:1571–3.PubMedCrossRef
33.
Litvak V, Ramsey SA, Rust AG, Zak DE, Kennedy KA, Lampano AE, Nykter M, Shmulevich I, Aderem A. Function of C/EBPdelta in a regulatory circuit that discriminates between transient and persistent TLR4-induced signals. Nat Immunol. 2009;10:437–43.PubMedPubMedCentralCrossRef
34.
Aksoy E, Taboubi S, Torres D, Delbauve S, Hachani A, Whitehead MA, Pearce WP, Berenjeno IM, Nock G, Filloux A, et al. The p110delta isoform of the kinase PI(3)K controls the subcellular compartmentalization of TLR4 signaling and protects from endotoxic shock. Nat Immunol. 2012;13:1045–54.PubMedPubMedCentralCrossRef
35.
Zanoni I, Ostuni R, Marek LR, Barresi S, Barbalat R, Barton GM, Granucci F, Kagan JC. CD14 controls the LPS-induced endocytosis of Toll-like receptor 4. Cell. 2011;147:868–80.PubMedPubMedCentralCrossRef
36.
Taguchi T, Mukai K. Innate immunity signalling and membrane trafficking. Curr Opin Cell Biol. 2019;59:1–7.PubMedCrossRef
37.
Eun HS, Lee BS, Chun K, Kang SJ, Kim SC, Gao B, Kunos G, Kim HM, Jeong WI, Husebye H, et al. The Rab11a GTPase controls Toll-like receptor 4-induced activation of interferon regulatory factor-3 on phagosomes. Nat Commun. 2010;33:583–96.
38.
Kim SY, Jeong JM, Kim SJ, Seo W, Kim MH, Choi WM, Yoo W, Lee JH, Shim YR, Yi HS, Lee YS. Pro-inflammatory hepatic macrophages generate ROS through NADPH oxidase 2 via endocytosis of monomeric TLR4-MD2 complex. Nat Commun. 2017;8:2247.PubMedPubMedCentralCrossRef
39.
Wu KC, Condon ND, Hill TA, Reid RC, Fairlie D, Lim J. Ras related protein Rab5a regulates complement C5a receptor trafficking, chemotaxis and chemokine secretion in human macrophages. J Innate Immun. 2023;15:468–84.PubMedPubMedCentralCrossRef
40.
Maganto-Garcia E, Punzon C, Terhorst C, Fresno M. Rab5 activation by Toll-like receptor 2 is required for Trypanosoma cruzi internalization and replication in macrophages. Traffic. 2008;9:1299–315.PubMedPubMedCentralCrossRef
41.
Barbieri MA, Roberts RL, Gumusboga A, Highfield H, Alvarez-Dominguez C, Wells A, Stahl PD. Epidermal growth factor and membrane trafficking. EGF receptor activation of endocytosis requires Rab5a. J Cell Biol. 2000;151:539–50.PubMedPubMedCentralCrossRef
42.
Zhang X, Chen C, Ling C, Luo S, Xiong Z, Liu X, Liao C, Xie P, Liu Y, Zhang L, et al. EGFR tyrosine kinase activity and Rab GTPases coordinate EGFR trafficking to regulate macrophage activation in sepsis. Cell Death Dis. 2022;13:934.PubMedPubMedCentralCrossRef
43.
Chen Z, Wang S, Chen Y, Shao Z, Yu Z, Mei S, Li Q. Integrin β3 modulates TLR4-mediated inflammation by regulation of CD14 expression in macrophages in septic condition. Shock. 2020;53:335–43.PubMedCrossRef
44.
Fleischmann-Struzek C, Goldfarb DM, Schlattmann P, Schlapbach LJ, Reinhart K, Kissoon N. The global burden of paediatric and neonatal sepsis: a systematic review. Lancet Respir Med. 2018;6:223–30.PubMedCrossRef
45.
Schultz MJ, Dunser MW, Dondorp AM, Adhikari NK, Iyer S, Kwizera A, Lubell Y, Papali A, Pisani L, Riviello BD, et al. Current challenges in the management of sepsis in ICUs in resource-poor settings and suggestions for the future. Intensive Care Med. 2017;43:612–24.PubMedCrossRef
46.
Sinha M, Jupe J, Mack H, Coleman TP, Lawrence SM, Fraley SI. Emerging technologies for molecular diagnosis of sepsis. Clin Microbiol Rev. 2018;31:10–128.CrossRef
47.
Opal SM, Laterre PF, Francois B, LaRosa SP, Angus DC, Mira JP, Wittebole X, Dugernier T, Perrotin D, Tidswell M, et al. Effect of eritoran, an antagonist of MD2-TLR4, on mortality in patients with severe sepsis: the ACCESS randomized trial. JAMA. 2013;309:1154–62.PubMedCrossRef
48.
Tse MT. Trial watch: sepsis study failure highlights need for trial design rethink. Nat Rev Drug Discov. 2013;12:334.PubMedCrossRef
49.
Prud’homme GJ, Glinka Y, Wang Q. Immunological GABAergic interactions and therapeutic applications in autoimmune diseases. Autoimmun Rev. 2015;14:1048–56.PubMedCrossRef
Metadata
Title
Propofol improves survival in a murine model of sepsis via inhibiting Rab5a-mediated intracellular trafficking of TLR4
Authors
Bo-Wei Zhou
Wen-Juan Zhang
Fang-Ling Zhang
Xiao Yang
Yu-Qi Ding
Zhi-Wen Yao
Zheng-Zheng Yan
Bing-Cheng Zhao
Xiao-Dong Chen
Cai Li
Ke-Xuan Liu
Publication date
01-12-2024
Publisher
BioMed Central
Published in
Journal of Translational Medicine / Issue 1/2024
Electronic ISSN: 1479-5876
DOI
https://doi.org/10.1186/s12967-024-05107-9

Other articles of this Issue 1/2024

Journal of Translational Medicine 1/2024 Go to the issue

Letter to the Editor

A scheme to underpin key mediator(s) in Salinosporamide(s) against pan-tumor via systems biology concept

Review

Impact of NQO1 dysregulation in CNS disorders

Research

The integration of multidisciplinary approaches revealed PTGES3 as a novel drug target for breast cancer treatment

Methodology

Adaptation of a standardized lifestyle intervention to maximize health outcomes in adolescent metabolic and bariatric surgery patients

Research

Asthma prediction via affinity graph enhanced classifier: a machine learning approach based on routine blood biomarkers

Research

Lack of shared neoantigens in prevalent mutations in cancer
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine
Image Credits