HMGB1 is an early and critical mediator in an animal model of uveitis induced by IRBP-specific T cells

Jiang, Guomin; Sun, Deming; Yang, Huan; Lu, Qin; Kaplan, Henry J.; Shao, Hui

doi:10.1189/jlb.0613337

Cited by 21 publications

(32 citation statements)

References 51 publications

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“…A specific combination of cytokine signals leads to the differentiation of naïve T cells into different effectors (Th1, Th2 and Th17) and regulatory T cell subsets. T cells can release HMGB1 in response to several stimuli or cell-cell contact in co-cultures (Jiang et al, 2013; Kawahara et al, 2007). In addition, HMGB1 released from DCs regulates polarization of CD4+ T cells (Messmer et al, 2004) and mediates cell-cell interactions (Kohka Takahashi et al, 2013).…”

Section: Hmgb1 Functionmentioning

confidence: 99%

HMGB1 in health and disease

Kang

Chen

Zhang

et al. 2014

Molecular Aspects of Medicine

823

828

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Complex genetic and physiological variations as well as environmental factors that drive emergence of chromosomal instability, development of unscheduled cell death, skewed differentiation, and altered metabolism are central to the pathogenesis of human diseases and disorders. Understanding the molecular bases for these processes is important for the development of new diagnostic biomarkers, and for identifying new therapeutic targets. In 1973, a group of non-histone nuclear proteins with high electrophoretic mobility was discovered and termed High-Mobility Group (HMG) proteins. The HMG proteins include three superfamilies termed HMGB, HMGN, and HMGA. High-mobility group box 1 (HMGB1), the most abundant and well-studied HMG protein, senses and coordinates the cellular stress response and plays a critical role not only inside of the cell as a DNA chaperone, chromosome guardian, autophagy sustainer, and protector from apoptotic cell death, but also outside the cell as the prototypic damage associated molecular pattern molecule (DAMP). This DAMP, in conjunction with other factors, thus has cytokine, chemokine, and growth factor activity, orchestrating the inflammatory and immune response. All of these characteristics make HMGB1 a critical molecular target in multiple human diseases including infectious diseases, ischemia, immune disorders, neurodegenerative diseases, metabolic disorders, and cancer. Indeed, a number of emergent strategies have been used to inhibit HMGB1 expression, release, and activity in vitro and in vivo. These include antibodies, peptide inhbitiors, RNAi, anti-coagulants, endogenous hormones, various chemical compounds, HMGB1-receptor and signaling pathway inhibition, artificial DNAs, physical strategies including vagus nerve stimulation and other surgical approaches. Future work further investigating the details of HMGB1 localizationtion, structure, post-translational modification, and identifccation of additional partners will undoubtedly uncover additional secrets regarding HMGB1’s multiple functions.

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Section: Hmgb1 Functionmentioning

confidence: 99%

HMGB1 in health and disease

Kang

Chen

Zhang

et al. 2014

Molecular Aspects of Medicine

823

828

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“…To assess the function of the T cells from WT and C3aR/C5aR KO mice with EAU, we compared the efficacy of the same number of WT and KO T cells in inducing retinal inflammation in naïve recipient mice. Using an established protocol [36,37], we activated the IRBP-specific T cells in vitro by culturing splenocytes from WT and KO mice with EAU using the same concentrations of IRBP peptide, together with IL-23, for 3 d. We then enriched the activated (blasted) T cells by Ficoll centrifugation and adoptively transferred a fixed number of the in vitro-activated (blasted) WT or KO T cells into naïve recipient mice. We evaluated EAU development by indirect ophthalmoscopy.…”

Section: Adoptive Transfer Of In Vitro-activated C3ar/c5ardeficient Tmentioning

confidence: 99%

Complement anaphylatoxin receptors C3aR and C5aR are required in the pathogenesis of experimental autoimmune uveitis

Zhang

Bell

et al. 2015

Journal of Leukocyte Biology

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Recent studies have suggested that reagents inhibiting complement activation could be effective in treating T cell mediated autoimmune diseases such as autoimmune uveitis. However, the precise role of the complement anaphylatoxin receptors (C3a and C5a receptors) in the pathogenesis of autoimmune uveitis remains elusive and controversial. We induced experimental autoimmune uveitis in mice deficient or sufficient in both C3a and C5a receptors and rigorously compared their retinal phenotype using various imaging techniques, including indirect ophthalmoscopy, confocal scanning laser ophthalmoscopy, spectral domain optical coherence tomography, topical endoscopic fundus imaging, and histopathological analysis. We also assessed retinal function using electroretinography. Moreover, we performed Ag-specific T cell recall assays and T cell adoptive transfer experiments to compare pathogenic T cell activity between wild-type and knockout mice with experimental autoimmune uveitis. These experiments showed that C3a receptor/C5a receptor-deficient mice developed much less severe uveitis than did control mice using all retinal examination methods and that these mice had reduced pathogenic T cell responses. Our data demonstrate that both complement anaphylatoxin receptors are important for the development of experimental autoimmune uveitis, suggesting that targeting these receptors could be a valid approach for treating patients with autoimmune uveitis.

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“…*P < 0.05. shown that elevation of HMGB1 in intraocular fluids has been shown to precede histopathologic changes in the EAU induced by adoptive transfer of uveitogenic T cells. 35 There were no significant differences in vitreous HMGB1 level and anterior and posterior segment inflammation scores between patients with ocular sarcoidosis treated with systemic corticosteroids and those without steroid treatment at the time of vitrectomy. These results suggest that vitrectomy was performed in the remission phase of uveitis in most of the sarcoidosis patients, irrespective of systemic treatment with corticosteroids.…”

Section: Discussionmentioning

confidence: 72%

“…In EAU, retinal cells release HMGB1 into the intraocular fluid via an interaction with pathogenic T cells, and systemic or local administration of anti-HMGB1 antibodies suppresses EAU by inhibiting pathogenic T-cell proliferation and their IFN-c and IL-17 production. 35 It is conceivable that Th1 cells that produce IFN-c promote release of HMGB1 in the vitreous in ocular sarcoidosis and that they are synergistically involved in the development of ocular inflammation.…”

Section: Discussionmentioning

confidence: 99%

“…Because HMGB1 released from retinal cells into extracellular matrix and intraocular fluid serves as a danger signal, administration of HMGB1 antagonists attenuates EAU via mechanisms including inhibition of uveitogenic T-cell proliferation and their IFN-c and IL-17 production. 24 Thus, it is possible that HMGB1 plays a role in granulomatous lesion formation in sarcoidosis. In this study, we measured vitreous levels of HMGB1 in patients with ocular sarcoidosis and compared them with those in patients with PDR and other vitreoretinal diseases.…”

mentioning

confidence: 99%

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Association of High-Mobility Group Box-1 With Th Cell–Related Cytokines in the Vitreous of Ocular Sarcoidosis Patients

Takeuchi

Taguchi

Sato

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. High-mobility group box-1 (HMGB1) is a nonhistone DNA-binding nuclear protein released from necrotic cells, which is also secreted by activated leukocytes and acts as a primary proinflammatory cytokine. In this study, we compared vitreous HMGB1 levels in ocular sarcoidosis with those in noninflammatory vitreoretinal diseases and evaluated its association with Th cell-related and proinflammatory cytokines. RESULTS. High-mobility group box-1 was detected in the vitreous of 23 of 24 patients (95.8%) with ocular sarcoidosis. Mean vitreous level of HMGB1 was the highest in the sarcoidosis group, followed by the PDR and ERM groups, with significant differences between the three groups. In the sarcoidosis group, vitreous levels of IL-6, IL-10, IL-31, IFN-c, sCD40L, and TNFa were significantly higher than those in the idiopathic ERM group, and IFN-c and sCD40L were significantly higher than those in the PDR group. Vitreous HMGB-1 level correlated significantly with IL-10, IFN-c, and sCD40L levels but not with IL-6, IL-17, IL-31, or TNFa levels.CONCLUSIONS. The vitreous level of HMGB1 is elevated in ocular sarcoidosis and is associated with vitreous levels of Th1-and regulatory T-related cytokines, but not with proinflammatory or Th17-related cytokines.

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HMGB1 is an early and critical mediator in an animal model of uveitis induced by IRBP-specific T cells

Cited by 21 publications

References 51 publications

HMGB1 in health and disease

HMGB1 in health and disease

Complement anaphylatoxin receptors C3aR and C5aR are required in the pathogenesis of experimental autoimmune uveitis

Association of High-Mobility Group Box-1 With Th Cell–Related Cytokines in the Vitreous of Ocular Sarcoidosis Patients

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