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HMGB1: what it is and how it could play a role in malignant pleural mesothelioma.

DEFINITION

HMGB1 is an acronym that stands for High Mobility Group Box 1. It is a protein that belongs to the high mobility group family, in other words, high electrophoretic mobility proteins. ("Electrophoretic mobility" can be defined as a measurement of the ability of a chemical substance to move when subjected to an electric field, and usually depends on various parameters such as the charge, size, conformation characteristics, the voltage applied to the field and the concentration of the electrophoretic medium).
This protein is also known as amphoterin or HMG1, and is a non-histone scaffold protein of chromatin.
HMGB1 also belongs to a subfamily of proteins that contain a domain involved in DNA binding, namely HMG-box.
Below is a three-dimensional image of the structure of this protein.

(from PDB: Protein Data Bank. https://www.rcsb.org/structure/1aab)

The HMGB1 gene is located on the long arm of chromasome 13 13q12.
The figure below shows the 5 exons of the HMGB1 gene in the form of small parallelepipeds (hollow for translated regions and solid for non-translated regions).
Part (B) of the figure below shows the 215 amino acid residues and is composed of three domains:  A box, B box and an acidic C-terminal tail. There are three cysteine residues at positions 23, 45 and 106, which regulate HMGB1 function in response to oxidative stress.
Part C of the figure shows HMGB1, which is loosely and transiently associated with nucleosomes. HMGB1 is important for spatial segregation and nuclear homeostatis.


(from He SJ, et al. Oncotarget. 2017)

In general, HMGB1 is ubiquitously expressed (only 10 times less than core histones). However, HMGB1 expression and subcellular localization varies depending on cell types and tissues and are developmentally regulated to cues from the environment.


(from He SJ, et al. Oncotarget. 2017)


MAIN FUNCTIONS

HMGB1 is found in large quantities within the nucleus of all eukaryotic cells and its main role is to remodel chromatin.
It has also recently been discovered that this protein is an important mediator in the inflammation process, especially in the case of cellular necrosis. As such, HMGB plays an important role in triggering inflammation but it also appears to be involved in innate and adaptive responses and in repairing tissue damage.
Cells undergoing stress actively secrete HMGB1, which is relocated from the nucelus to the cytoplasm and then to secretory lysosomes or directly to the extracellular space.


(from Bianchi ME, et al. Immunol Rev. 2017)

The HMGB1 protein can be passively released from dead cells, as shown on the right in the figure. In other cases, it is actively secreted as a result of cellular stress, as shown on the left.
Under normal conditions, this protein is located in the nucleus in a reduced and unacetylated form. Following tissue damage, this unmodified protein is released from dead cells and subsequently converted into the disulfide-HMGB1 form by spontaneous oxidation, or through reactive oxygen species (ROS), which are produced in abundance by inflammatory cells.
Leukocytes can also secrete HMGB1, which is first released into the cytoplasm and subsequently acetylated or phosphorylated, and then passes into the extracellular space after being transformed. This often occurs after it has been loaded into secretory lysosomes or through a little-known mechanism into non-hematopoietic cells.
Secreted HMGB1 can be distinguished from passively released HMGB1 (in yellow), due to the acetylated state, shown in green in the figure. The secreted form is also oxidized.
The figure at left shows the pathway of LPS- and interferon-induced HMGB1 secretions after a bacterial or viral infection.
Immune cells are first recruited to the damaged tissue site and are then activitated after arriving at the site.

The HMGB1 protein supports tissue repair by coordinating the switch of macrophages to a tissue-healing phenotype, activation and profileration of stem cells, and neoangiogenesis. Unfortunately, this protein similarly helps repair tissue of all damaged cells, including tumor cells.


(from Bianchi ME, et al. Immunol Rev. 2017)

The figure above shows the role of HMGB  in tissue repair.
As shown, this protein plays an important role during muscle injury.
HMGB1 is released from damaged or necrotic muscle cells. Under these conditions, this protein can also promote the recruitment of immune system cells such as leukocytes by forming heterocomplexes with CXCL12. Inflammation occurs when the leukocytes arrive at the damaged tissue site. HMGB1 is then oxidized to disulfide through free oxygen radicals, which are formed after infiltration by the leukocytes. HMGB1 also activates the leukocytes to promote the release of a series of pro-inflammatory cytokines and chemokines, but loses its ability to form heterocomplexes with CXCL12.
After resolving the inflammatory state, the tissue-healing phenotype macrophages release HMGB1, which can activate stem cells and promote angiogenesis as well as coordinate muscle injury repair.

HMGB1 AND CANCER

The HMGB1 protein appears to play an important role in cancer progression.
The figure below shows how HMGB1 can interact biologically to promote carcinogenesis.
In the extracellular space, as shown in part A, HMGB1 signals through receptors such as RAGE, TLRs, TIM3 and CXCR4, driving cell proliferation, invasion and angiogenesis, metastasis, apoptosis evasion, inflammation and immunity. The interaction between HMGB1 and CXCR4 is dependent on CXCL12. TLR9 is initially localized on the endoplasmic reticulum (ER) and then redistributes to endosomes upon stimulation with CpG-DNA via an HMGB1- dependent pathway.
In part B, HMGB1 is present at the cell surface and promotes cell migration and tumor- cell metastasis.
In the cytoplasm, as shown in part C of the figure, HMGB1 regulates autophagy and promotes cell proliferation.
In the nucleus, as shown in part D, HMGB1 acts as a DNA chaperone participating in DNA repair and transcription. HMGB1 can also interact with transcription factors such as p53, p73 and RB and enhance their activities. Nuclear HMGB1 enhances telomerase activity and modulates telomere homeostatis.


(from He SJ, et al. Oncotarget. 2017)

HMGB1 AND MALIGNANT PLEURAL MESOTHELIOMA

HMGB1 is highly involved in tumor biology.
HMGB1 appears to be associated with mesothelioma. In this neoplasm, asbestos causes inflammation of the mesothelium but the biomolecular pathways underlying this inflammatory- neoplastic process are not completely known.
However, it was recently discovered that asbestos induces the death of mesothelial cells by necrosis, with the resulting release of HMGB1 into the extracellular space and recall of inflammatory cells.

The persistence of the asbestos fibers is one of the main causes of the perpetuation of inflammation in the pleura and often the lungs of subjects who have been exposed to this carcinogen and then develop MPM. High levels of HMGB1 have been seen in the blood of subjects exposed to asbestos as well as those with MPM, demonstrating that this protein could be involved in these carcinogenesis and inflammation processes. Here too, it is not fully understood how persistent inflammation can induce carcinogenesis but some studies suggest that macrophages play a role in cell survival, demonstrated by the fact that macrophages have been found in abundance in neoplastic tissue.
The figure below shows the pro- or anti-tumoral activity of HMGB1.
In part A, mesothelial cells are damaged by exposure to asbestos and induce programmed necrotic cell death, resulting in the release of HMGB1.
Part B shows the pro-tumoral activity of HMGB1, which bends TLR4 and produces a state of chronic inflammation leading to malignant transformation. Macrophages are present in the mesothelial tissue and HMGB1 is constitutively secreted by the mesothelioma cells.
Part C shows the anti-tumoral characteristics of this protein. The question mark shown in the figure means that the mechanisms involving HMGB1 and the pathogenesis of mesothelioma have never beeen fully investigated. However, the activity of this protein against various tumors has been widely documented. HMGB1 is secreted by the cells and probably involved in the mechanisms that lead to the responses of B- and T-cells to immunological memory.


(from Bianchi ME, et al. Immunol Rev. 2017)

CONCLUSIONS

Further research into this protein will lead to a greater understanding of the pathogenesis of cancer.
Many researchers are specifically trying to determine the actual rol of HMGB1 in MPM to better define the carcinogenesis of this disease.
Future research also aims to design therapeutic approaches that may involve this protein or pathways activated by it.

REFERENCE

1. Janeway CA Jr, Medzhitov R. Innate immune recognition. Annu Rev Immunol. 2002;20:197‐216.

2. Matzinger P. The danger model: A renewed sense of self. Science. 2002;296:301‐305.

3. Scaffidi P, Misteli T, Bianchi ME. Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature. 2002;418:191‐ 195.

4. Wang H, Bloom O, Zhang M, et al. HMG-1 as a late mediator of endotoxin lethality in mice. Science. 1999;285:248‐251.

5. Falciola L, Spada F, Calogero S, et al. High mobility group 1 (HMG1) protein is not stably associated with the chromosomes of somatic cells. J Cell Biol. 1997;137:19‐26.

6. Rovere-Querini P, Capobianco A, Scaffidi P, et al. HMGB1 is an endogenous immune adjuvant released by necrotic cells. EMBO Rep. 2004;5:825‐ 830.

7. Messmer D, Yang H, Telusma G, et al. High mobility group box protein 1: An endogenous signal for dendritic cell maturation and Th1 polarization J Immunol. 2004;173:307‐313.

8. Dumitriu IE, Baruah P, Valentinis B, et al. Release of High Mobility Group Box 1 by dendritic cells controls T cell activation via the receptor for
advanced glycation end products. J Immunol. 2005;174:7506‐7515.

9. Dumitriu IE, Bianchi ME, Bacci M, Manfredi AA, Rovere-Querini P. The secretion of HMGB1 is required for the migration of maturing dendritic cells. J Leukoc Biol. 2007;81:84‐91.

10. Chen GY, Tang J, Zheng P, Liu Y. CD24 and Siglec-10 selectively repress tissue damage-induced immune responses. Science. 2009;323:1722‐ 1725.

11. Chiba S, Baghdadi M, Akiba H, et al. Tumor-infiltrating DCs suppress nucleic acid-mediated innate immune responses through interactions between the receptor TIM-3 and the alarmin HMGB1. Nat Immunol. 2012;3:832‐842.

12. Gardella S, Andrei C, Ferrera D, et al. The nuclear protein HMGB1 is secreted by monocytes via a non- classical, vesicle-mediated secretory pathway. EMBO Rep. 2002;3:995‐1001.

13. Bonaldi T, Talamo F, Scaffidi P, et al. Monocytic cells hyperacetylate chromatin protein HMGB1 to redirect it towards secretion. EMBO J.
2003;22:5551‐5560.

14. Oh YJ, Youn JH, Ji Y, et al. HMGB1 is phosphorylated by classical protein kinase C and is secreted by a calcium-dependent mechanism. J
Immunol. 2009;182:5800‐5809.

15. Tsung A, Klune JR, Zhang X, et al. HMGB1 release induced by liver ischemia involves Toll-like receptor 4 dependent reactive oxygen species production and calcium-mediated signaling. J Exp Med. 2007;204:2913‐ 2923.

16. Lu B, Antoine DK, Kwan K, et al. JAK/STAT1 signaling promotes HMGB1 hyperacetylation and nuclear translocation. Proc Natl Acad Sci USA. 2014;111:3068‐3073.

17. Hoppe G, Talcott KE, Bhattacharya SK, Crabb JW, Sears JE. Molecular basis for the redox control of nuclear transport of the structural chromatin protein Hmgb1. Exp Cell Res. 2006;312:3526‐3538.

18. Venereau E, Casalgrandi M, Schiraldi M, et al. Mutually exclusive redox forms of HMGB1 promote cell recruitment or proinflammatory cytokine release. J Exp Med. 2012;209:1519‐1528.

19. Schiraldi M, Raucci A, Munoz LM, et al. HMGB1 promotes recruitment of inflammatory cells to damaged tissues by forming a complex with CXCL12 and signaling via CXCR4. J Exp Med. 2012;209:551‐563.

20. Pawig L, Klasen C, Weber C, Bernhagen J, Noels H. Diversity and inter-connections in the CXCR4 chemokine receptor/ligand family: Molecular perspectives. Front Immunol. 2015;6:429.

21. Collins PJ, McCully ML, Martinez-Munoz L, et al. Epithelial chemokine CXCL14 synergizes with CXCL12 via allosteric modulation of CXCR4. FASEB J. 2017;31:3084‐3097.

22. Yang H, Wang H, Ju Z, et al. MD-2 is required for disulfide HMGB1- dependent TLR4 signaling. J Exp Med. 2015;212:5‐14.

23. Yang H, Hreggvidsdottir HS, Palmblad K, et al. A critical cysteine is required for HMGB1 binding to Toll- like receptor 4 and activation of macrophage cytokine release. Proc Natl Acad Sci USA. 2010;107:11942‐11947.

24. Abraham E, Arcaroli J, Carmody A, Wang H, Tracey KJ. HMG-1 as a mediator of acute lung inflammation. J Immunol. 2000;165:2950‐2954.

25. Tsung A, Sahai R, Tanaka H, et al. The nuclear factor HMGB1 mediates hepatic injury after murine liver ischemia-reperfusion. J Exp Med. 2005;201:1135‐1143.

26. Muhammad S, Barakat W, Stoyanov S, et al. The HMGB1 receptor RAGE mediates ischemic brain damage. J Neurosci. 2008;28:12023‐12031.

27. Weng H, Deng Y, Xie Y, Liu H, Gong F. Expression and significance of HMGB1, TLR4 and NF-kappaB p65 in human epidermal tumors. BMC Cancer. 2013;13:311.

28. Maroso M, Balosso S, Ravizza T, et al. Toll-like receptor 4 and high mobility group box-1 are involved in ictogenesis and can be targeted to reduce seizures. Nat Med. 2010;16:413‐ 419.

29. Agalave NM, Larsson M, Abdelmoaty S, et al. Spinal HMGB1 induces TLR4-mediated
long-lasting hypersensitivity and glial activation and regulates pain- like behavior in experimental arthritis. Pain. 2014;155:1802‐1813.

30. Ma F, Kouzoukas DE, Meyer- Siegler KL, Westlund KN, Hunt DE, Vera PL. Disulfide high mobility group box- 1 causes bladder pain through bladder Toll-like receptor 4. BMC Physiol. 2017;17:6.

31. Tian J, Avalos AM, Mao SY, et al. Toll-like receptor 9-dependent activation by DNA-containing immune complexes is mediated by HMGB1 and RAGE. Nat Immunol. 2007;8:487‐496.

32. Ivanov S, Dragoi AM, Wang X, et al. A novel role for HMGB1 in TLR9- mediated inflammatory responses to CpG-DNA. Blood. 2007;110:1970‐1981.

33. Urbonaviciute V, Furnrohr BG, Meister S, et al. Induction of inflammatory and immune responses by HMGB1-nucleosome complexes: Implications for the pathogenesis of SLE. J Exp Med. 2008;295:3007‐3018.

34. Parkkinen J, Raulo E, Merenmies J, et al. Amphoterin, the 30 kDa protein in a family of HMG1-type polypeptides. J Biol Chem. 1993;268:19726‐19738.

35. Sessa L, Gatti E, Zeni F, et al. The receptor for advanced glycation end-products (RAGE) is only present in mammals, and belongs to a family of cell adhesion molecules (CAMs). PLoS ONE. 2014;9:e86903.

36. Fritz G. RAGE: A single receptor fits multiple ligands. Trends Biochem Sci. 2011;36:625‐632.

37. Raucci A, Cugusi S, Antonelli A, et al. A soluble form of the receptor for advanced glycation endproducts (RAGE) is produced by proteolytic cleavage of the membrane- bound form by the sheddase a disintegrin and metalloprotease 10 (ADAM10). FASEB J. 2008;22:3716‐3727.

38. Braley A, Kwak T, Jules J, Harja E, Landgraf R, Hudson BI. Regulation of receptor for advanced glycation end products (RAGE) ectodomain shedding and its role in cell function. J Biol Chem. 2016;291:12057‐12073.

39. Kokkola R, Andersson A, Mullins G, et al. RAGE is the major receptor for the proinflammatory activity of HMGB1 in rodent macrophages. Scand J Immunol. 2005;61:1‐9.

40. Fiuza C, Bustin M, Talwar S, et al. Inflammatory promoting activity of HMGB1 on human microvascular endothelial cells. Blood. 2002;27:2652‐2660.

41. Kew RR, Penzo M, Habiel DM, Marcu KB. The IKKalpha-dependent NF- kappaB p52/RelB noncanonical pathway is essential to sustain a CXCL12 autocrine loop in cells migrating in response to HMGB1. J Immunol. 2012;188:2380‐2386.

42. Vogel S, Bodenstein R, Chen Q, et al. Platelet-derived HMGB1 is a critical mediator of thrombosis. J Clin Invest. 2015;125:4638‐4654.

43. Stark K, Philippi V, Stockhausen S, et al. Disulfide HMGB1 derived from platelets coordinates venous thrombosis in mice. Blood. 2016;128:2435‐2449.

44. Mitola S, Belleri M, Urbinati C, et al. Cutting edge: Extracellular high mobility group box-1 protein is a proangiogenic cytokine. J Immunol. 2006;176:12‐15.

45. Venereau E, Schiraldi M, Uguccioni M, Bianchi ME. HMGB1 and leukocyte migration during trauma and sterile inflammation. Mol Immunol. 2013;55:76‐82.

46. Venereau E, Ceriotti C, Bianchi ME. DAMPs from cell death to new life. Front Immunol. 2015;6:422.

47. Dormoy-Raclet V, Cammas A, Celona B, et al. HuR and miR-1192 regulate myogenesis by modulating the translation of HMGB1 mRNA. Nat Commun. 2013;4:2388.

48. van Beijnum JR, Dings RP, van der Linden E, et al. Gene expression of tumor angiogenesis dissected: Specific targeting of colon cancer angiogenic vasculature. Blood. 2006;108:2339‐2348.

49. Campana L, Santarella F, Esposito A, et al. Leukocyte HMGB1 is required for vessel remodeling in regenerating muscles. J Immunol. 2014;192:5257‐5264.

50. Palumbo R, Sampaolesi M, De Marchis F, et al. Extracellular HMGB1, a signal of tissue damage, induces mesoangioblast migration and proliferation. J Cell Biol. 2004;164:441‐449.

51. Limana F, Germani A, Zacheo A, et al. Exogenous high-mobility group box 1 protein induces myocardial regeneration after infarction via enhanced cardiac C-kit+ cell proliferation and differentiation. Circ Res. 2005;97:e73‐83.

52. Meng E, Guo Z, Wang H, et al. High mobility group box 1 protein inhibits the proliferation of human mesenchymal stem cells and promotes their migration and differentiation along osteoblastic pathway. Stem Cells Dev. 2008;17:805‐813.

53. Lotfi R, Eisenbacher J, Solgi G, et al. Human mesenchymal stem cells respond to native but not oxidized damage associated molecular pattern molecules from necrotic (tumor) material. Eur J Immunol. 2011;41:2021‐ 2028.

54. Tamai K, Yamazaki T, Chino T, et al. PDGFR{alpha}-positive cells in bone marrow are mobilized by high mobility group box 1 (HMGB1) to regenerate injured epithelia. Proc Natl Acad Sci USA. 2011;108:6609‐6614.

55. Chavakis E, Hain A, Vinci M, et al. High-mobility group box 1 activates integrin-dependent

56. Hanahan D, Weinberg RA. Hallmarks of cancer: The next generation. Cell. 2011;144:646‐674.

57. Carbone M, Yang H. Mesothelioma: Recent highlights. Ann Transl Med. 2017;5:238.

58. Yang H, Rivera Z, Jube S, et al. Programmed necrosis induced by asbestos in human mesothelial cells causes high-mobility group box 1 protein release and resultant inflammation. Proc Natl Acad Sci USA. 2010;107:12611‐12616.

59. Napolitano A, Antoine DJ, Pellegrini L, et al. HMGB1 and its hyper-acetylated isoform are sensitive and specific serum biomarkers to detect asbestos exposure and to identify mesothelioma patients. Clin Cancer Res. 2016;22:3087‐3096.

60. Cornelissen R, Lievense LA, Maat AP, et al. Ratio of intratumoral macrophage phenotypes is a prognostic factor in epithelioid malignant pleural mesothelioma. PLoS ONE. 2014;9:e106742.

61. Jube S, Rivera ZS, Bianchi ME, et al. Cancer cell secretion of the DAMP protein HMGB1 supports progression in malignant mesothelioma. Cancer Res. 2012;72:3290‐3301.

62. Yang H, Pellegrini L, Napolitano A, et al. Aspirin delays mesothelioma growth by inhibiting HMGB1-mediated tumor progression. Cell Death Dis. 2015;6:e1786.

63. Pellegrini L, Xue J, Larson D, et al. HMGB1 targeting by ethyl pyruvate suppresses malignant phenotype of human mesothelioma. Oncotarget. 2017;8:22649‐22661.

64. Cottone L, Capobianco A, Gualteroni C, et al. Leukocytes recruited by tumor-derived HMGB1 sustain peritoneal carcinomatosis. Oncoimmunol. 2016;5:e1122860.

65. Mittal D, Saccheri F, Venereau E, Pusterla T, Bianchi ME, Rescigno M. TLR4-mediated skin carcinogenesis is dependent on immune and radioresistant cells. EMBO J. 2010;29:2242‐2252.

66. Bald T, Quast T, Landsberg J, et al. Ultraviolet-radiation- induced inflammation promotes angiotropism and metastasis in melanoma. Nature. 2014;507:109‐113.

67. Guo ZS, Liu Z, Bartlett DL, Tang D, Lotze MT. Life after death: Targeting high mobility group box 1 in emergent cancer therapies. Am J Cancer Res. 2013;3:1‐20.

68. Cottone L, Capobianco A, Gualteroni C, et al. 5-Fluorouracil causes leukocytes attraction in the peritoneal cavity by activating autophagy and HMGB1 release in colon carcinoma cells. Int J Cancer. 2015;136:1381‐1389.

69. Galluzzi L, Buque A, Kepp O, Zitvogel L, Kroemer G. Immunogenic cell death in cancer and infectious disease. Nat Rev Immunol. 2017;17:97‐ 111.

70. Demaria S, Ng B, Devitt ML, et al. Ionizing radiation inhibition of distant untreated tumors (abscopal effect) is immune mediated. Int J Radiat Oncol Biol Phys. 2004;58:862‐ 870.

71. Casares N, Pequignot MO, Tesniere A, et al. Caspase-dependent immunogenicity of doxorubicin-induced tumor cell death. J Exp Med. 2005;202:1691‐1701.

72. Krysko DV, Garg AD, Kaczmarek A, Krysko O, Agostinis P, Vandenabeele P. Immunogenic cell death and DAMPs in cancer therapy. Nat Rev Cancer. 2012;12:860‐875.

73. Apetoh L, Ghiringhelli F, Tesniere A, et al. Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat Med. 2007;13:1050‐ 1059.

74. Ladoire S, Penault-Llorca F, Senovilla L, et al. Combined evaluation of LC3B puncta and HMGB1 expression predicts residual risk of relapse after adjuvant chemotherapy in breast cancer. Autophagy. 2015;11:1878‐1890.

75. Yamazaki T, Hannani D, Poirier- Colame V, et al. Defective immunogenic cell death of HMGB1-deficient tumors: Compensatory therapy with TLR4 agonists. Cell Death Differ. 2014;21:69‐78.

76. Sistigu A, Yamazaki T, Vacchelli E, et al. Cancer cell- autonomous contribution of type I interferon signaling to the efficacy of chemotherapy. Nat Med. 2014;20:1301‐1309.

77. Garg AD, Krysko DV, Verfaillie T, et al. A novel pathway combining calreticulin exposure and ATP secretion in immunogenic cancer cell death. EMBO J. 2012;31:1062‐1079.

78. Trisciuoglio L, Bianchi ME. Several nuclear events during apoptosis depend on caspase-3 activation but do not constitute a common pathway. PLoS ONE. 2009;4:e6234.

79. Kazama H, Ricci JE, Herndon JM, Hoppe G, Green DR, Ferguson TA. Induction of immunological tolerance by apoptotic cells requires caspase- dependent oxidation of high-mobility group box-1 protein. Immunity. 2008;29:21‐32.

80. Goodwin GH, Sanders C, Johns EW. A new group of chromatin- associated proteins with a high content of acidic and basic amino acids. Eur J Biochem. 1973;38:14‐19.

81. Agresti A, Bianchi ME. HMGB proteins and gene expression. Curr Op Genet Develop. 2003;13:170‐178.

82. Sessa L, Bianchi ME. The evolution of High Mobility Group Box (HMGB) chromatin proteins in multicellular animals. Gene. 2007;387:133‐140.

83. Giavara S, Kosmidou E, Hande MP, et al. Yeast Nhp6A/B and mammalian Hmgb1 facilitate the maintenance of genome stability. Curr Biol. 2005;15:68‐72.

84. Celona B, Weiner A, Di Felice F, et al. Substantial histone reduction modulates genomewide nucleosomal occupancy and global transcriptional output. PLoS Biol. 2011;9:e1001086.

85. Choi HW, Manohar M, Manosalva P, Tian M, Moreau M, Klessig DF. Activation of plant innate immunity by extracellular high mobility group box 3 and its inhibition by salicylic acid. PLoS Pathog. 2016;12:e1005518.

86. Li J, Zhang Y, Xiang Z, Xiao S, Yu F, Yu Z. High mobility group box 1 can enhance NF-κB activation and act as a pro-inflammatory molecule in the Pacific oyster, Crassostrea gigas. Fish Shellfish Immunol. 2013;35:63‐70.

87. Venereau E, De Leo F, Mezzapelle R, Careccia G, Musco G, Bianchi ME. HMGB1 as biomarker and drug target. Pharmacol Res. 2016;111:534‐544.

88. Bianchi ME, Manfredi AA. How macrophages ring the inflammation alarm. Proc Natl Acad Sci USA. 2014;111:2866‐2867. homing of endothelial progenitor cells. Circ Res. 2007;100:204‐212.

89. He SJ, Cheng J, Feng X, Yu Y, Tian L, Huang Q. The dual role and therapeutic potential of high-mobility group box 1 in cancer. Oncotarget. 2017 May 16;8(38):64534-64550. doi: 10.18632/oncotarget.17885. eCollection 2017 Sep 8.

90. Ferrari, S., Finelli, P., Rocchi, M., Bianchi, M. E. The active gene that encodes human high mobility group 1 protein (HMG1) contains introns and maps to chromosome 13. Genomics 35: 367-371, 1996. PMID 8661151

91. Bianchi ME, Crippa MP, Manfredi AA, Mezzapelle R, Rovere Querini P, Venereau E1. High-mobility group box 1 protein orchestrates responses to tissue damage via inflammation, innate and adaptive immunity, and tissue repair. Immunol Rev. 2017 Nov;280(1):74-82. doi: 10.1111/imr.12601.