ArticleArteriosclerosis, thrombosis, and vascular biology2017
Cardiotonic Steroids Stimulate Macrophage Inflammatory Responses Through a Pathway Involving CD36, TLR4, and Na/K-ATPase.
Article in Arteriosclerosis, thrombosis, and vascular biology, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers, 1 of them a synthesis that pooled it.
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Who cites it
22 citing papers in PubMed, 1 synthesis or guideline pooled it, 38 citations in OpenAlex.
- The role of CD36 in immune function: bridging innate and adaptive responses.Frontiers in immunology · 2026Pooled it
- Lanatoside C ameliorates DSS-induced colitis with improved intestinal barrier integrity and reduced M1 macrophage polarization.Scientific reports · 2026Article
- Sodium Danshensu Inhibits Macrophage Inflammation in Atherosclerosis via the miR-200a-3p/MEKK3/NF-κB Signaling Pathway.Molecular neurobiology · 2025Article
- Mechanisms mediating effects of cardiotonic steroids in mammalian blood cells.Frontiers in pharmacology · 2025Review
- Na,K-ATPase mediated and cardiotonic induced signaling in health and disease.Frontiers in physiology · 2025Review
- Deciphering the Role of CD36 in Gestational Diabetes Mellitus: Linking Fatty Acid Metabolism and Inflammation in Disease Pathogenesis.Journal of inflammation research · 2025Review
- Sodium, Potassium-Adenosine Triphosphatase as a Potential Target of the Anti-Tuberculosis Agents, Clofazimine and Bedaquiline.International journal of molecular sciences · 2024Article
- Sensational site: the sodium pump ouabain-binding site and its ligands.American journal of physiology. Cell physiology · 2024Review
- Targeting Cysteine Oxidation in Thrombotic Disorders.Antioxidants (Basel, Switzerland) · 2024Review
- The Na/K-ATPase role as a signal transducer in lung inflammation.Frontiers in immunology · 2023Review
- Article
- CD36, a signaling receptor and fatty acid transporter that regulates immune cell metabolism and fate.The Journal of experimental medicine · 2022Review
- Neuroinflammation and Neutrophils: Modulation by Ouabain.Frontiers in pharmacology · 2022Review
- Molecular mechanisms of Na,K-ATPase dysregulation driving alveolar epithelial barrier failure in severe COVID-19.American journal of physiology. Lung cellular and molecular physiology · 2021Article
- Epithelial and Endothelial Adhesion of Immune Cells Is Enhanced by Cardiotonic Steroid Signaling Through NaJournal of the American Heart Association · 2020Article
- Proinflammatory Effects of Cardiotonic Steroids Mediated by NKA α-1 (Na+/K+-ATPase α-1)/Src Complex in Renal Epithelial Cells and Immune Cells.Hypertension (Dallas, Tex. : 1979) · 2019Article
- FcRγ deficiency improves survival in experimental sepsis by down-regulating TLR4 signaling pathway.Immunologic research · 2019Article
- Toll-Like Receptor 4 and Blood Pressure: Lessons From Animal Studies.Frontiers in physiology · 2019Article
- Reporting Sex and Sex Differences in Preclinical Studies.Arteriosclerosis, thrombosis, and vascular biology · 2018Article
- The Na/K-ATPase Signaling: From Specific Ligands to General Reactive Oxygen Species.International journal of molecular sciences · 2018Review
Corrections and comments
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
Abstract
objectiveCirculating levels of cardiotonic steroids (CTS) are elevated in various chronic inflammatory conditions, but the role of CTS in inflammation remains largely unknown. We have previously shown that the CTS ouabain stimulates proinflammatory responses in murine macrophages. In this study, we aim to explore the mechanism how CTS induce proinflammatory responses in primary murine and human macrophages. APPROACH AND
resultsUsing both murine peritoneal macrophages and human monocyte-derived macrophages, we demonstrated that ouabain activated NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells), leading to proinflammatory cytokine (eg, MCP-1 [monocyte chemotactic protein 1], TNF-α [tumor necrosis factor-α], IL-1β [interleukin-1β], and IL-6) production. By applying siRNA techniques and murine peritoneal macrophages isolated from genetically modified mice, we showed that macrophages partially deficient in Na/K-ATPase, the receptor for CTS, or fully deficient in the scavenger receptor CD36 or TLR4 (Toll-like receptor) were resistant to ouabain-induced NF-κB activation, suggesting an indispensable role of these 3 receptors in this pathway. Mechanistically, this effect of ouabain was independent of the ion transport function of the Na/K-ATPase. Instead, ouabain stimulated a signaling complex, including Na/K-ATPase, CD36, and TLR4. Subsequently, TLR4 recruited MyD88 adaptor protein for NF-κB activation. Furthermore, intraperitoneal injection of ouabain into mice specifically recruited Ly6C
conclusionsCTS activate NF-κB leading to proinflammatory cytokine production in primary macrophages through a signaling complex, including CD36, TLR4, and Na/K-ATPase. These findings warrant further studies on endogenous CTS in chronic inflammatory diseases, such as atherosclerosis.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.