Transcriptomic Profiling Reveals That HMGB1 Induces Macrophage Polarization Different from Classical M1

Overview

Journal Biomolecules

Publisher MDPI

Specialties Biochemistry
Molecular Biology

Date 2022 Jun 24

PMID 35740904

Authors

Heshuang Qu

Rebecka Heinback

Henna Salo

Ewoud Ewing

Alexander Espinosa

Cecilia Aulin

Helena Erlandsson Harris

Affiliations

Soon will be listed here.

Abstract

Macrophages are key inflammatory immune cells that display dynamic phenotypes and functions in response to their local microenvironment. In different conditions, macrophage polarization can be induced by high-mobility group box 1 (HMGB1), a nuclear DNA-binding protein that activates innate immunity via the Toll-like receptor (TLR) 4, the receptor for advanced glycation end products (RAGE), and C-X-C chemokine receptor (CXCR) 4. This study investigated the phenotypes of murine bone-marrow-derived macrophages (BMDMs) stimulated with different HMGB1 redox isoforms using bulk RNA sequencing (RNA-Seq). Disulfide HMGB1 (dsHMGB1)-stimulated BMDMs showed a similar but distinct transcriptomic profile to LPS/IFNγ- and LPS-stimulated BMDMs. Fully reduced HMGB1 (frHMGB1) did not induce any significant transcriptomic change. Interestingly, compared to LPS/IFNγ- and LPS-, dsHMGB1-stimulated BMDMs showed lipid metabolism and foam cell differentiation gene set enrichment, and oil red O staining revealed that both dsHMGB1 and frHMGB1 alleviated oxidized low-density lipoprotein (oxLDL)-induced foam cells formation. Overall, this work, for the first time, used transcriptomic analysis by RNA-Seq to investigate the impact of HMGB1 stimulation on BMDM polarization. Our results demonstrated that dsHMGB1 and frHMGB1 induced distinct BMDM polarization phenotypes compared to LPS/IFNγ- and LPS- induced phenotypes.

Citing Articles

HMGB1 in Septic Muscle Atrophy: Roles and Therapeutic Potential for Muscle Atrophy and Regeneration.

Qi S, Wu Q, Xiang P, Hou C, Kang Z, Chen M J Cachexia Sarcopenia Muscle. 2025; 16(1):e13711.

PMID: 39963819 PMC: 11833301. DOI: 10.1002/jcsm.13711.

Lactate and lactylation in macrophage metabolic reprogramming: current progress and outstanding issues.

Xu B, Liu Y, Li N, Geng Q Front Immunol. 2024; 15:1395786.

PMID: 38835758 PMC: 11148263. DOI: 10.3389/fimmu.2024.1395786.

Damage-mediated macrophage polarization in sterile inflammation.

Koncz G, Jenei V, Toth M, Varadi E, Kardos B, Bacsi A Front Immunol. 2023; 14:1169560.

PMID: 37465676 PMC: 10351389. DOI: 10.3389/fimmu.2023.1169560.

Quantitative proteomics analysis of COVID-19 patients: Fetuin-A and tetranectin as potential modulators of innate immune responses.

Alghanem B, Mansour F, Shaibah H, Almuhalhil K, Almourfi F, Alamri H Heliyon. 2023; 9(4):e15224.

PMID: 37064481 PMC: 10082967. DOI: 10.1016/j.heliyon.2023.e15224.

Macrophages in aseptic loosening: Characteristics, functions, and mechanisms.

Cong Y, Wang Y, Yuan T, Zhang Z, Ge J, Meng Q Front Immunol. 2023; 14:1122057.

PMID: 36969165 PMC: 10030580. DOI: 10.3389/fimmu.2023.1122057.

References

McNelis J, Olefsky J . Macrophages, immunity, and metabolic disease. Immunity. 2014; 41(1):36-48. DOI: 10.1016/j.immuni.2014.05.010. View

Lyu J, Xie D, Bhatia T, Leak R, Hu X, Jiang X . Microglial/Macrophage polarization and function in brain injury and repair after stroke. CNS Neurosci Ther. 2021; 27(5):515-527. PMC: 8025652. DOI: 10.1111/cns.13620. View

Schierbeck H, Pullerits R, Pruunsild C, Fischer M, Holzinger D, Laestadius A . HMGB1 levels are increased in patients with juvenile idiopathic arthritis, correlate with early onset of disease, and are independent of disease duration. J Rheumatol. 2013; 40(9):1604-13. DOI: 10.3899/jrheum.120987. View

Oishi Y, Manabe I . Macrophages in inflammation, repair and regeneration. Int Immunol. 2018; 30(11):511-528. DOI: 10.1093/intimm/dxy054. View

Wunderer F, Traeger L, Sigurslid H, Meybohm P, Bloch D, Malhotra R . The role of hepcidin and iron homeostasis in atherosclerosis. Pharmacol Res. 2020; 153:104664. PMC: 7066581. DOI: 10.1016/j.phrs.2020.104664. View

Murray P . Macrophage Polarization. Annu Rev Physiol. 2016; 79:541-566. DOI: 10.1146/annurev-physiol-022516-034339. View

Kuhbandner K, Hammer A, Haase S, Terbrack E, Hoffmann A, Schippers A . MAdCAM-1-Mediated Intestinal Lymphocyte Homing Is Critical for the Development of Active Experimental Autoimmune Encephalomyelitis. Front Immunol. 2019; 10:903. PMC: 6503766. DOI: 10.3389/fimmu.2019.00903. View

Hubert P, Roncarati P, Demoulin S, Pilard C, Ancion M, Reynders C . Extracellular HMGB1 blockade inhibits tumor growth through profoundly remodeling immune microenvironment and enhances checkpoint inhibitor-based immunotherapy. J Immunother Cancer. 2021; 9(3). PMC: 7959241. DOI: 10.1136/jitc-2020-001966. View

Weischenfeldt J, Porse B . Bone Marrow-Derived Macrophages (BMM): Isolation and Applications. CSH Protoc. 2011; 2008:pdb.prot5080. DOI: 10.1101/pdb.prot5080. View

10.

Hreggvidsdottir H, Lundberg A, Aveberger A, Klevenvall L, Andersson U, Harris H . High mobility group box protein 1 (HMGB1)-partner molecule complexes enhance cytokine production by signaling through the partner molecule receptor. Mol Med. 2011; 18:224-30. PMC: 3320135. DOI: 10.2119/molmed.2011.00327. View

11.

Scaffidi P, Misteli T, Bianchi M . Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature. 2002; 418(6894):191-5. DOI: 10.1038/nature00858. View

12.

Liu T, Zhang L, Joo D, Sun S . NF-κB signaling in inflammation. Signal Transduct Target Ther. 2017; 2. PMC: 5661633. DOI: 10.1038/sigtrans.2017.23. View

13.

Yang H, Wang H, Ju Z, Ragab A, Lundback P, Long W . MD-2 is required for disulfide HMGB1-dependent TLR4 signaling. J Exp Med. 2015; 212(1):5-14. PMC: 4291531. DOI: 10.1084/jem.20141318. View

14.

Goldstein R, Bruchfeld A, Yang L, Qureshi A, Gallowitsch-Puerta M, Patel N . Cholinergic anti-inflammatory pathway activity and High Mobility Group Box-1 (HMGB1) serum levels in patients with rheumatoid arthritis. Mol Med. 2007; 13(3-4):210-5. PMC: 1899837. DOI: 10.2119/2006–00108.Goldstein. View

15.

Yang H, Wang H, Andersson U . Targeting Inflammation Driven by HMGB1. Front Immunol. 2020; 11:484. PMC: 7099994. DOI: 10.3389/fimmu.2020.00484. View

16.

Salo H, Qu H, Mitsiou D, Aucott H, Han J, Zhang X . Disulfide and Fully Reduced HMGB1 Induce Different Macrophage Polarization and Migration Patterns. Biomolecules. 2021; 11(6). PMC: 8229957. DOI: 10.3390/biom11060800. View

17.

Wang H, Bloom O, Zhang M, Vishnubhakat J, Ombrellino M, Che J . HMG-1 as a late mediator of endotoxin lethality in mice. Science. 1999; 285(5425):248-51. DOI: 10.1126/science.285.5425.248. View

18.

Schippers A, Leuker C, Pabst O, Kochut A, Prochnow B, Gruber A . Mucosal addressin cell-adhesion molecule-1 controls plasma-cell migration and function in the small intestine of mice. Gastroenterology. 2009; 137(3):924-33. DOI: 10.1053/j.gastro.2009.05.039. View

19.

Martinez F, Gordon S . The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000Prime Rep. 2014; 6:13. PMC: 3944738. DOI: 10.12703/P6-13. View

20.

Wu H, Chen Z, Chen J, Pei L, Xie J, Wei Z . High Mobility Group B-1 (HMGB-1) Promotes Apoptosis of Macrophage-Derived Foam Cells by Inducing Endoplasmic Reticulum Stress. Cell Physiol Biochem. 2018; 48(3):1019-1029. DOI: 10.1159/000491970. View