Interleukins-27 Aggravates Liver Injury by Impairing the Antimicrobial Response of Macrophages via the Promotion of Mitochondrial Dysfunction in the Context of Sepsis
Yuehua You
Department of Critical Care Medicine , The First Affiliated Hospital of Chongqing Medical University , Chongqing , China , cqmu.edu.cn
The Chongqing Key Laboratory of Translational Medicine in Major Metabolic Diseases , The First Affiliated Hospital of Chongqing Medical University , Chongqing , China , cqmu.edu.cn
Search for more papers by this authorYuyan Li
Department of Critical Care Medicine , The First Affiliated Hospital of Chongqing Medical University , Chongqing , China , cqmu.edu.cn
Department of Critical Care Medicine , The First People’s Hospital of Chongqing High-tech Zone , Chongqing , China
Laboratory Research Center , The First Affiliated Hospital of Chongqing Medical University , Chongqing , China , cqmu.edu.cn
Search for more papers by this authorLin Ye
Department of Critical Care Medicine , The First Affiliated Hospital of Chongqing Medical University , Chongqing , China , cqmu.edu.cn
The Chongqing Key Laboratory of Translational Medicine in Major Metabolic Diseases , The First Affiliated Hospital of Chongqing Medical University , Chongqing , China , cqmu.edu.cn
Search for more papers by this authorCorresponding Author
Fang Xu
Department of Critical Care Medicine , The First Affiliated Hospital of Chongqing Medical University , Chongqing , China , cqmu.edu.cn
Search for more papers by this authorCorresponding Author
Jing Fan
Department of Critical Care Medicine , The First Affiliated Hospital of Chongqing Medical University , Chongqing , China , cqmu.edu.cn
Search for more papers by this authorYuehua You
Department of Critical Care Medicine , The First Affiliated Hospital of Chongqing Medical University , Chongqing , China , cqmu.edu.cn
The Chongqing Key Laboratory of Translational Medicine in Major Metabolic Diseases , The First Affiliated Hospital of Chongqing Medical University , Chongqing , China , cqmu.edu.cn
Search for more papers by this authorYuyan Li
Department of Critical Care Medicine , The First Affiliated Hospital of Chongqing Medical University , Chongqing , China , cqmu.edu.cn
Department of Critical Care Medicine , The First People’s Hospital of Chongqing High-tech Zone , Chongqing , China
Laboratory Research Center , The First Affiliated Hospital of Chongqing Medical University , Chongqing , China , cqmu.edu.cn
Search for more papers by this authorLin Ye
Department of Critical Care Medicine , The First Affiliated Hospital of Chongqing Medical University , Chongqing , China , cqmu.edu.cn
The Chongqing Key Laboratory of Translational Medicine in Major Metabolic Diseases , The First Affiliated Hospital of Chongqing Medical University , Chongqing , China , cqmu.edu.cn
Search for more papers by this authorCorresponding Author
Fang Xu
Department of Critical Care Medicine , The First Affiliated Hospital of Chongqing Medical University , Chongqing , China , cqmu.edu.cn
Search for more papers by this authorCorresponding Author
Jing Fan
Department of Critical Care Medicine , The First Affiliated Hospital of Chongqing Medical University , Chongqing , China , cqmu.edu.cn
Search for more papers by this authorAbstract
Background and Aims: Plasma interleukin (IL)-27 is an important mediator of acute hepatic injury (AHI) associated with sepsis. Mitochondria contribute to the proper regulation of macrophage phagocytosis. In this study, we investigated the effect of IL-27 on mitochondrial function and the antimicrobial response of macrophages in sepsis-associated AHI.
Methods: Wild-type (WT) and IL-27 receptor WSX-1 deficient (IL-27R−/−) mice underwent cecal ligation and puncture (CLP). The severity of hepatic injury, inflammatory cytokine levels, hepatic pyroptosis, and bacterial load in the liver and blood were assessed 24 h after CLP. In vitro, RAW264.7 cells and peritoneal macrophages were treated with lipopolysaccharide (LPS) and/or IL-27. The phagocytosis and killing functions of macrophages were detected. Mitochondrial function and mitophagy were detected using western blot, glutathione (GSH)/malondialdehyde (MDA) content measurement, fluorescence staining, and JC-1 staining in vivo and in vitro. After treatment with nicotinamide mononucleotide (NMN, NAD + precursor), a pharmacologic agent that improves mitochondrial function, the inflammatory response, hepatic injury, and hepatic pyroptosis were assessed.
Results: IL-27R−/− mice exhibited a marked reduction in hepatic injury, pyroptosis (based on cleaved GSDMD and cleaved Caspases 1 protein levels), and systemic inflammation (based on serum IL-6, IL-10, and TNF-α levels) compared to WT mice following CLP. After CLP, mice lacking IL-27R displayed significantly higher bacterial clearance and greater local infection control. Subsequent studies demonstrated that IL-27 directly impaired the LPS-induced bacterial phagocytosis, killing capacity, and mitochondrial function of macrophages. Finally, enhanced mitochondrial function using NMN in vivo significantly alleviated pathological liver injury and inflammation.
Conclusions: These findings indicated that IL-27 impairs the bacterial phagocytosis capacity of macrophages by aggravating mitochondrial dysfunction to aggravate AHI during sepsis.
References
- 1 Laura E., Andrew R., and Waleed A., et al.Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021, Critical Care Medicine. (2021) 49, no. 11, e1063–e1143.
- 2 Cutuli S. L., Cascarano L., and Lazzaro P., et al.Antimicrobial Exposure in Critically Ill Patients With Sepsis-Associated Multi-Organ Dysfunction Requiring Extracorporeal Organ Support: A Narrative Review, Microorganisms. (2023) 11, no. 2, 473.
- 3 Kubes P. and Jenne C., Immune Responses in the Liver, Annual Review of Immunology. (2018) 36, 247–277, https://doi.org/10.1146/annurev-immunol-051116-052415, 2-s2.0-85045945296.
- 4 Strnad P., Tacke F., Koch A., and Trautwein C., Liver—Guardian, Modifier and Target of Sepsis, Nature Reviews Gastroenterology & Hepatology. (2017) 14, no. 1, 55–66, https://doi.org/10.1038/nrgastro.2016.168, 2-s2.0-85001831564.
- 5 Dusabimana T., Je J., Yun S. P., Kim H. J., Kim H., and Park S. W., GOLPH3 Promotes Endotoxemia-Induced Liver and Kidney Injury Through Golgi Stress-Mediated Apoptosis and Inflammatory Response, Cell Death & Disease. (2023) 14, no. 7, https://doi.org/10.1038/s41419-023-05975-x, 458.
- 6 Zhang X., Liu H., Hashimoto K., Yuan S., and Zhang J., The Gut-Liver Axis in Sepsis: Interaction Mechanisms and Therapeutic Potential, Critical Care. (2022) 26, no. 1, https://doi.org/10.1186/s13054-022-04090-1, 213.
- 7 Guilliams M. and Scott C. L., Liver Macrophages in Health and Disease, Immunity. (2022) 55, no. 9, 1515–1529, https://doi.org/10.1016/j.immuni.2022.08.002.
- 8 Beyer D., Hoff J., Sommerfeld O., Zipprich A., Gaßler N., and Press A. T., The Liver in Sepsis: Molecular Mechanism of Liver Failure and Their Potential for Clinical Translation, Molecular Medicine. (2022) 28, no. 1, https://doi.org/10.1186/s10020-022-00510-8, 84.
- 9 Shapouri-Moghaddam A., Mohammadian S., and Vazini H., et al.Macrophage Plasticity, Polarization, and Function in Health and Disease, Journal of Cellular Physiology. (2018) 233, no. 9, 6425–6440, https://doi.org/10.1002/jcp.26429, 2-s2.0-85044125236.
- 10 Shan Z. and Ju C., Hepatic Macrophages in Liver Injury, Frontiers in Immunology. (2020) 11, https://doi.org/10.3389/fimmu.2020.00322, 322.
- 11 Villarino A. V., Huang E., and Hunter C. A., et al.Understanding the Pro- and Anti-Inflammatory Properties of IL-27, The Journal of Immunology. (2004) 173, no. 2, 715–720, https://doi.org/10.4049/jimmunol.173.2.715, 2-s2.0-3142709474.
- 12 Morita Y., Masters E. A., Schwarz E. M., and Muthukrishnan G., Interleukin-27 and Its Diverse Effects on Bacterial Infections, Frontiers in Immunology. (2021) 12, https://doi.org/10.3389/fimmu.2021.678515, 678515.
- 13 Liao K., Wang J., and Li Z., et al.Transcriptomic Analysis Identifies a Pan-Cancer Association of IL27 Expression with Cancer Prognosis and Immune Microenvironment, Genes & Diseases. (2023) 10, no. 2, 393–395, https://doi.org/10.1016/j.gendis.2022.08.016.
- 14 Zahra B., Mahshid Z., Morvarid A., and Abbas G., IL-27, A Pleiotropic Cytokine for Fine-Tuning the Immune Response in Cancer, International Reviews of Immunology. (2020) 40, no. 5, 319–329.
- 15 Fan J., Zhang Y. C., and Zheng D. F., et al.IL-27 Is Elevated in Sepsis With Acute Hepatic Injury and Promotes Hepatic Damage and Inflammation in the CLP Model, Cytokine. (2019) 127, 154936.
- 16 Nedel W., Deutschendorf C., and Portela L. V. C., Sepsis-Induced Mitochondrial Dysfunction: A Narrative Review, World Journal of Critical Care Medicine. (2023) 12, no. 3, 139–152, https://doi.org/10.5492/wjccm.v12.i3.139.
- 17 Lyu Y., Wang T., Huang S., and Zhang Z., Mitochondrial Damage-Associated Molecular Patterns and Metabolism in the Regulation of Innate Immunity, Journal of Innate Immunity. (2023) 15, no. 1, 665–679, https://doi.org/10.1159/000533602.
- 18 Long X., Xiaoyu Y., and Yuanxin Z., et al.Macrophage Polarization Mediated by Mitochondrial Dysfunction Induces Adipose Tissue Inflammation in Obesity, International Journal of Molecular Sciences. (2022) 23, no. 16, 9252.
- 19 Sowrirajan B., Saito Y., and Poudyal D., et al.Interleukin-27 Enhances the Potential of Reactive Oxygen Species Generation From Monocyte-Derived Macrophages and Dendritic Cells by Induction of p47(phox), Scientific Reports. (2017) 7, no. 1, https://doi.org/10.1038/srep43441, 2-s2.0-85014117085, 43441.
- 20 Cao T., Ni R., and Ding W., et al.Nicotinamide Mononucleotide as a Therapeutic Agent to Alleviate Multi-Organ Failure in Sepsis, Journal of Translational Medicine. (2023) 21, no. 1, https://doi.org/10.1186/s12967-023-04767-3, 883.
- 21 Perelman A., Wachtel C., Cohen M., Haupt S., Shapiro H., and Tzur A., JC-1: Alternative Excitation Wavelengths Facilitate Mitochondrial Membrane Potential Cytometry, Cell Death & Disease. (2012) 3, no. 11, https://doi.org/10.1038/cddis.2012.171, 2-s2.0-84870487329, e430.
- 22 Singer M., Deutschman C. S., and Seymour C. W., et al.The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3), JAMA. (2016) 315, no. 8, 801–810, https://doi.org/10.1001/jama.2016.0287, 2-s2.0-84959273475.
- 23 Woźnica E. A., Inglot M., Woźnica R. K., and Łysenko L., Liver Dysfunction in Sepsis, Advances in Clinical and Experimental Medicine. (2018) 27, no. 4, 547–551, https://doi.org/10.17219/acem/68363, 2-s2.0-85048831183.
- 24 Sun J., Zhang J., and Wang X., et al.Gut-Liver Crosstalk in Sepsis-Induced Liver Injury, Critical Care. (2020) 24, no. 1, https://doi.org/10.1186/s13054-020-03327-1, 614.
- 25 Giamarellos-Bourboulis E. J., Aschenbrenner A. C., and Bauer M., et al.The Pathophysiology of Sepsis and Precision-Medicine-Based Immunotherapy, Nature Immunology. (2024) 25, no. 1, 19–28, https://doi.org/10.1038/s41590-023-01660-5.
- 26 Akoumianaki T., Vaporidi K., and Diamantaki E., et al.Uncoupling of IL-6 Signaling and LC3-Associated Phagocytosis Drives Immunoparalysis During Sepsis, Cell Host & Microbe. (2021) 29, no. 8, 1277–1293.e6, https://doi.org/10.1016/j.chom.2021.06.002.
- 27 Wang Y., Zhao J., Yao Y., Zhao D., and Liu S., Interleukin-27 as a Diagnostic Biomarker for Patients With Sepsis: A Meta-Analysis, BioMed Research International. (2021) 2021, 5516940.
- 28 Gramignoli R., Ranade A. R., Venkataramanan R., and Strom S. C., Effects of Pro-Inflammatory Cytokines on Hepatic Metabolism in Primary Human Hepatocytes, International Journal of Molecular Sciences. (2022) 23, no. 23, 14880.
- 29 Zhao Q., Gong Z., and Wang J., et al.A Zinc- and Calcium-Rich Lysosomal Nanoreactor Rescues Monocyte/Macrophage Dysfunction Under Sepsis, Advanced Science. (2023) 10, no. 6, https://doi.org/10.1002/advs.202205097, e2205097.
- 30 Wang Z., Wu Z., and Wang H., et al.An Immune Cell Atlas Reveals the Dynamics of Human Macrophage Specification During Prenatal Development, Cell. (2023) 186, no. 20, 4454–4471.e19, https://doi.org/10.1016/j.cell.2023.08.019.
- 31 Wirtz S., Tubbe I., and Galle P. R., et al.Protection From Lethal Septic Peritonitis by Neutralizing the Biological Function of Interleukin 27, The Journal of Experimental Medicine. (2006) 203, no. 8, 1875–1881, https://doi.org/10.1084/jem.20060471, 2-s2.0-33746931178.
- 32 Cao J., Xu F., and Lin S., et al.IL-27 Controls Sepsis-Induced Impairment of Lung Antibacterial Host Defence, Thorax. (2014) 69, no. 10, 926–937, https://doi.org/10.1136/thoraxjnl-2014-205777, 2-s2.0-84907034129.
- 33 Geng J., Shi Y., and Zhang J., et al.TLR4 Signalling via Piezo1 Engages and Enhances the Macrophage Mediated Host Response During Bacterial Infection, Nature Communications. (2021) 12, no. 1, https://doi.org/10.1038/s41467-021-23683-y, 3519.
- 34 Li J. P., Wu H., and Xing W., et al.Interleukin-27 as a Negative Regulator of Human Neutrophil Function, Scandinavian Journal of Immunology. (2010) 72, no. 4, 284–292, https://doi.org/10.1111/j.1365-3083.2010.02422.x, 2-s2.0-77956313444.
- 35 Supinski G. S., Schroder E. A., and Callahan L. A., Mitochondria and Critical Illness, Chest. (2020) 157, no. 2, 310–322, https://doi.org/10.1016/j.chest.2019.08.2182.
- 36 Jiang W., Le J., and Wang P.-Y., et al.Extracellular Acidity Reprograms Macrophage Metabolism and Innate Responsiveness, The Journal of Immunology. (2021) 206, no. 12, 3021–3031, https://doi.org/10.4049/jimmunol.2100014.
- 37 Yang S. Y., Yang Y., and Wang F. F., et al.TREM2 Dictates Antibacterial Defense and Viability of Bone Marrow-Derived Macrophages During Bacterial Infection, American Journal of Respiratory Cell and Molecular Biology. (2021) 65, no. 2, 176–188, https://doi.org/10.1165/rcmb.2020-0521OC.
- 38 Ma L., Han T., and Zhan Y.-A., Mechanism and Role of Mitophagy in the Development of Severe Infection, Cell Death Discov. (2024) 10, https://doi.org/10.1038/s41420-024-01844-4, 88.
- 39 Danish P., Franck M., and Valérie D., et al.Inhibition of Mitophagy Drives Macrophage Activation and Antibacterial Defense During Sepsis, The Journal of clinical investigation. (2020) 130, no. 11, 5858–5874.
- 40 Yildirim R. M. and Seli E., Mitochondria as Therapeutic Targets in Assisted Reproduction, Human Reproduction. (2024) 39, no. 10, 2147–2159, https://doi.org/10.1093/humrep/deae170.
- 41 Luo C., Ding W., Yang C., Zhang W., Liu X., and Deng H., Nicotinamide Mononucleotide Administration Restores Redox Homeostasis via the Sirt3-Nrf2 Axis and Protects Aged Mice From Oxidative Stress-Induced Liver Injury, Journal of Proteome Research. (2022) 21, no. 7, 1759–1770, https://doi.org/10.1021/acs.jproteome.2c00167.
- 42 Yan Z., Niu L., Wang S., Gao C., and Pan S., Intestinal Piezo1 Aggravates Intestinal Barrier Dysfunction During Sepsis by Mediating Ca2+ Influx, Journal of Translational Medicine. (2024) 22, no. 1, https://doi.org/10.1186/s12967-024-05076-z, 332.
- 43 Zhang X., Du Y., and Sun Q., et al.Calcium/Calmodulin-Dependent Protein Kinase Regulates the PINK1/Parkin and DJ-1 Pathways of Mitophagy during Sepsis, The FASEB Journal. (2017) 31, no. 10, 4382–4395, https://doi.org/10.1096/fj.201601096RRR, 2-s2.0-85030628096.
- 44 Ye Y., Huang X., and Zhang Y., et al.Calcium Influx Blocked by SK&F 96365 Modulates the LPS plus IFN-γ-Induced Inflammatory Response in Murine Peritoneal Macrophages, International Immunopharmacology. (2012) 12, no. 2, 384–393, https://doi.org/10.1016/j.intimp.2011.12.011, 2-s2.0-84862823880.
- 45 Görlach A., Bertram K., Hudecova S., and Krizanova O., Calcium and ROS: A Mutual Interplay, Redox Biology. (2015) 6, 260–271, https://doi.org/10.1016/j.redox.2015.08.010, 2-s2.0-84940043387.
- 46 Atcha H., Jairaman A., and Holt J. R., et al.Mechanically Activated Ion Channel Piezo1 Modulates Macrophage Polarization and Stiffness Sensing, Nature Communications. (2021) 12, no. 1, https://doi.org/10.1038/s41467-021-23482-5, 3256.
- 47 Pradhan G., Raj Abraham P., Shrivastava R., and Mukhopadhyay S., Calcium Signaling Commands Phagosome Maturation Process, International Reviews of Immunology. (2019) 38, no. 2, 57–69, https://doi.org/10.1080/08830185.2019.1592169, 2-s2.0-85066411099.
