Induction of Immunological Tolerance by Apoptotic Cells Requires Caspase-dependent Oxidation of High-mobility Group Box-1 Protein

Overview

Journal Immunity

Publisher Cell Press

Specialty Allergy & Immunology

Date 2008 Jul 18

PMID 18631454

Citations 298

Authors

Hirotaka Kazama

Jean-Ehrland Ricci

John M Herndon

George Hoppe

Douglas R Green

Thomas A Ferguson

Affiliations

Soon will be listed here.

Abstract

The mammalian immune system discriminates between modes of cell death; necrosis often results in inflammation and adaptive immunity, whereas apoptosis tends to be anti-inflammatory and promote immune tolerance. We have examined apoptosis for the features responsible for tolerance; specifically, we looked at the roles of caspases and mitochondria. Our results show that caspase activation targeted the mitochondria to produce reactive oxygen species (ROS), which were critical to tolerance induction by apoptotic cells. ROS oxidized the potential danger signal high-mobility group box-1 protein (HMGB1) released from dying cells and thereby neutralized its stimulatory activity. Apoptotic cells failed to induce tolerance and instead stimulated immune responses by scavenging or by mutating a mitochondrial caspase target protein when ROS activity was prohibited. Similarly, blocking sites of oxidation in HMGB1 prevented tolerance induction by apoptotic cells. These results suggest that caspase-orchestrated mitochondrial events determine the impact of apoptotic cells on the immune response.

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.

ROS anchor PAMPs-mediated extracellular HMGB1 self-association and its dimerization enhances pro-inflammatory signaling.

Kwak M, Han M, Lee Y, Choi S, Kim J, Park I Redox Biol. 2025; 80:103521.

PMID: 39908862 PMC: 11847140. DOI: 10.1016/j.redox.2025.103521.

High Mobility Group Box 1 (HMGB1): Molecular Signaling and Potential Therapeutic Strategies.

Datta S, Rahman M, Koka S, Boini K Cells. 2024; 13(23).

PMID: 39682695 PMC: 11639863. DOI: 10.3390/cells13231946.

Triggering immunogenic death of cancer cells by nanoparticles overcomes immunotherapy resistance.

Mei T, Ye T, Huang D, Xie Y, Xue Y, Zhou D Cell Oncol (Dordr). 2024; 47(6):2049-2071.

PMID: 39565509 DOI: 10.1007/s13402-024-01009-6.

Small-molecule GSDMD agonism in tumors stimulates antitumor immunity without toxicity.

Fontana P, Du G, Zhang Y, Zhang H, Vora S, Hu J Cell. 2024; 187(22):6165-6181.e22.

PMID: 39243763 PMC: 11648675. DOI: 10.1016/j.cell.2024.08.007.

References

Hoppe G, Talcott K, Bhattacharya S, Crabb J, Sears J . Molecular basis for the redox control of nuclear transport of the structural chromatin protein Hmgb1. Exp Cell Res. 2006; 312(18):3526-38. DOI: 10.1016/j.yexcr.2006.07.020. View

Tesniere A, Panaretakis T, Kepp O, Apetoh L, Ghiringhelli F, Zitvogel L . Molecular characteristics of immunogenic cancer cell death. Cell Death Differ. 2007; 15(1):3-12. DOI: 10.1038/sj.cdd.4402269. View

Andersson U, Erlandsson-Harris H, Yang H, Tracey K . HMGB1 as a DNA-binding cytokine. J Leukoc Biol. 2002; 72(6):1084-91. View

Heath W, Kurts C, Miller J, Carbone F . Cross-tolerance: a pathway for inducing tolerance to peripheral tissue antigens. J Exp Med. 1998; 187(10):1549-53. PMC: 2212282. DOI: 10.1084/jem.187.10.1549. View

Lakhani S, Masud A, Kuida K, Porter Jr G, Booth C, Mehal W . Caspases 3 and 7: key mediators of mitochondrial events of apoptosis. Science. 2006; 311(5762):847-51. PMC: 3738210. DOI: 10.1126/science.1115035. View

Czura C, Tracey K . Targeting high mobility group box 1 as a late-acting mediator of inflammation. Crit Care Med. 2003; 31(1 Suppl):S46-50. DOI: 10.1097/00003246-200301001-00007. View

Griffith T, Kazama H, Vanoosten R, Earle Jr J, Herndon J, Green D . Apoptotic cells induce tolerance by generating helpless CD8+ T cells that produce TRAIL. J Immunol. 2007; 178(5):2679-87. DOI: 10.4049/jimmunol.178.5.2679. View

Martin S, Green D . Protease activation during apoptosis: death by a thousand cuts?. Cell. 1995; 82(3):349-52. DOI: 10.1016/0092-8674(95)90422-0. View

Millar D, Garza K, Odermatt B, Elford A, Ono N, Li Z . Hsp70 promotes antigen-presenting cell function and converts T-cell tolerance to autoimmunity in vivo. Nat Med. 2003; 9(12):1469-76. DOI: 10.1038/nm962. View

10.

Obeid M, Panaretakis T, Joza N, Tufi R, Tesniere A, Van Endert P . Calreticulin exposure is required for the immunogenicity of gamma-irradiation and UVC light-induced apoptosis. Cell Death Differ. 2007; 14(10):1848-50. DOI: 10.1038/sj.cdd.4402201. View

11.

Obeid M, Tesniere A, Ghiringhelli F, Fimia G, Apetoh L, Perfettini J . Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat Med. 2006; 13(1):54-61. DOI: 10.1038/nm1523. View

12.

Ricci J, Gottlieb R, Green D . Caspase-mediated loss of mitochondrial function and generation of reactive oxygen species during apoptosis. J Cell Biol. 2003; 160(1):65-75. PMC: 2172744. DOI: 10.1083/jcb.200208089. View

13.

Kurts C, Heath W, Kosaka H, Miller J, Carbone F . The peripheral deletion of autoreactive CD8+ T cells induced by cross-presentation of self-antigens involves signaling through CD95 (Fas, Apo-1). J Exp Med. 1998; 188(2):415-20. PMC: 2212451. DOI: 10.1084/jem.188.2.415. View

14.

Messmer D, Yang H, Telusma G, Knoll F, Li J, Messmer B . High mobility group box protein 1: an endogenous signal for dendritic cell maturation and Th1 polarization. J Immunol. 2004; 173(1):307-13. DOI: 10.4049/jimmunol.173.1.307. View

15.

Li J, Kokkola R, Tabibzadeh S, Yang R, Ochani M, Qiang X . Structural basis for the proinflammatory cytokine activity of high mobility group box 1. Mol Med. 2003; 9(1-2):37-45. PMC: 1430376. View

16.

Bonfoco E, Stuart P, Brunner T, Lin T, Griffith T, Gao Y . Inducible nonlymphoid expression of Fas ligand is responsible for superantigen-induced peripheral deletion of T cells. Immunity. 1998; 9(5):711-20. DOI: 10.1016/s1074-7613(00)80668-8. View

17.

Ricci J, Munoz-Pinedo C, Fitzgerald P, Bailly-Maitre B, Perkins G, Yadava N . Disruption of mitochondrial function during apoptosis is mediated by caspase cleavage of the p75 subunit of complex I of the electron transport chain. Cell. 2004; 117(6):773-86. DOI: 10.1016/j.cell.2004.05.008. View

18.

Fleury C, Mignotte B, Vayssiere J . Mitochondrial reactive oxygen species in cell death signaling. Biochimie. 2002; 84(2-3):131-41. DOI: 10.1016/s0300-9084(02)01369-x. View

19.

Ott M, Gogvadze V, Orrenius S, Zhivotovsky B . Mitochondria, oxidative stress and cell death. Apoptosis. 2007; 12(5):913-22. DOI: 10.1007/s10495-007-0756-2. View

20.

Fadok V, Bratton D, Konowal A, Freed P, Westcott J, Henson P . Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-beta, PGE2, and PAF. J Clin Invest. 1998; 101(4):890-8. PMC: 508637. DOI: 10.1172/JCI1112. View