Inhibiting HMGB1-RAGE axis prevents pro-inflammatory macrophages/microglia polarization and affords neuroprotection after spinal cord injury

Fan, Hong; Tang, Hai‐Bin; Chen, Zhe; Wang, Huqing; Zhang, Lei; Jiang, Yu; Li, Tao; Yang, Caifeng; Wang, Xiaoya; Li, Xia; Wu, Shengxi; Zhang, Guilian

doi:10.1186/s12974-020-01973-4

Cited by 141 publications

(95 citation statements)

References 66 publications

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“…Furthermore, the disintegration of astrocytes, detected by the GFAP upregulation, can stimulate the overexpression of other inflammatory mediators involved in neurological damage. Necroptotic astrocytes release the HMGB1 protein and stimulate the HMGB1-RAGE axis [47] , [48] that can induce inflammatory events leading to organ dysfunctions, including the brain. The binding of HMGB1 to RAGE promotes the transcription of inflammatory factors including the NFκB and MAPK pathways [49] , and its sustained activation causes cell death by stimulating the production of reactive oxygen species [50] .…”

Section: Discussionmentioning

confidence: 99%

Oxidative stress and inflammatory markers in patients with COVID-19: Potential role of RAGE, HMGB1, GFAP and COX-2 in disease severity

Passos

Heimfarth

Monteiro

et al. 2022

International Immunopharmacology

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Background SARS-CoV-2 infection can lead to the abnormal induction of cytokines and a dysregulated hyperinflammatory state that is implicated in disease severity and risk of death. There are several molecules present in blood associated with immune cellular response, inflammation, and oxidative stress that could be used as severity markers in respiratory viral infections such as COVID-19. However, there is a lack of clinical studies evaluating the role of oxidative stress-related molecules including glial fibrillary acidic protein (GFAP), the receptor for advanced glycation end products (RAGE), high mobility group box-1 protein (HMGB1) and cyclo-oxygenase-2 (COX-2) in COVID-19 pathogenesis. Aim To evaluate the role of oxidative stress-related molecules in COVID-19. Method An observational study with 93 Brazilian participants from September 2020 to April 2021, comprising 23 patients with COVID-19 admitted to intensive care unit (ICU), 19 outpatients with COVID-19 with mild to moderate symptoms, 17 individuals reporting a COVID-19 history, and 34 healthy controls. Blood samples were taken from all participants and western blot assay was used to determine the RAGE, HMGB1, GFAP, and COX-2 immunocontent. Results We found that GFAP levels were higher in patients with severe or critical COVID-19 compared to outpatients (p = 0.030) and controls (p < 0.001). A significant increase in immunocontents of RAGE (p < 0.001) and HMGB1 (p < 0.001) were also found among patients admitted to the ICU compared to healthy controls, as well as an overexpression of the inducible COX-2 (p < 0.001). In addition, we found a moderate to strong correlation between RAGE, GFAP and HMGB1 proteins. Conclusion SARS-CoV-2 infection induces the upregulation of GFAP, RAGE, HMGB1, and COX-2 in patients with the most severe forms of COVID-19.

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Section: Discussionmentioning

confidence: 99%

Oxidative stress and inflammatory markers in patients with COVID-19: Potential role of RAGE, HMGB1, GFAP and COX-2 in disease severity

Passos

Heimfarth

Monteiro

et al. 2022

International Immunopharmacology

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“…In all of the cells mentioned, and additionally, in the endothelial and other vascular cells, the activation of NADPH oxidases (Nox) [ 92 ] leads to enhanced ROS formation, which also stimulates inflammatory responses inasmuch as other causes of oxidative stress do. Independently of cell type, any dying cell can release proinflammatory DAMP factors (damage-associated molecular pattern), such as histone H1 [ 93 ] or HMBG1 (high-mobility group box 1) [ 94 , 95 , 96 ]. Both of them activate microglia, and the suppression of HMBG1 can reduce ROS formation and proinflammatory cytokine release.…”

Section: Melatonin Influences Glial and Glial-neuronal Interactionsmentioning

confidence: 99%

Melatonin and Microglia

Hardeland

2021

IJMS

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Melatonin interacts in multiple ways with microglia, both directly and, via routes of crosstalk with astrocytes and neurons, indirectly. These effects of melatonin are of relevance in terms of antioxidative protection, not only concerning free-radical detoxification, but also in prevention of processes that cause, promote, or propagate oxidative stress and neurodegeneration, such as overexcitation, toxicological insults, viral and bacterial infections, and sterile inflammation of different grades. The immunological interplay in the CNS, with microglia playing a central role, is of high complexity and includes signaling toward endothelial cells and other leukocytes by cytokines, chemokines, nitric oxide, and eikosanoids. Melatonin interferes with these processes in multiple signaling routes and steps. In addition to canonical signal transduction by MT1 and MT2 melatonin receptors, secondary and tertiary signaling is of relevance and has to be considered, e.g., via the upregulation of sirtuins and the modulation of pro- and anti-inflammatory microRNAs. Many details concerning the modulation of macrophage functionality by melatonin are obviously also applicable to microglial cells. Of particular interest is the polarization toward M2 subtypes instead of M1, i.e., in favor of being anti-inflammatory at the expense of proinflammatory activities, which is well-documented in macrophages but also applies to microglia.

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“…Neutralizing HMGB1 with anti-HMGB1 antibody and reduced HMGB1 in the conditioned medium results in decreased M2 polarization of macrophages. RAGE exists on the membrane of macrophages and is the surface receptor of HMGB1, which can bind by HMGB1 to regulate macrophage polarization [34,35]. In this study, we found that anti-REAG can prevent M2 polarization of macrophages which induced by HMGB1.…”

Section: Discussionmentioning

confidence: 51%

Positive feedback loop of HMGB1 and tumor-associated macrophages plays a key role in osteosarcoma metastasis

Hou

Lei

et al. 2021

Preprint

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Background Numerous studies have demonstrated the important roles of tumor-associated macrophages (TAMs) in osteosarcoma metastasis. In osteosarcoma, higher levels of HMGB1 correlate with osteosarcoma progression. However, whether HMGB1 is involved in the polarization of M2 macrophages into M1 macrophages in osteosarcoma still remains largely unknown. Methods HMGB1 and CD206 mRNA expression was measured by qRT-PCR in osteosarcoma tissues and cells. HMGB1 and RAGE protein expression was measured by western blotting. Osteosarcoma migration was measured using a Transwell and wound-healing assay. Osteosarcoma invasion was measured using a Transwell assay. Macrophage subtypes were detected using flow cytometry. Results HMGB1 is aberrantly overexpressed in osteosarcoma, and positively correlates with the TNM III & IV stages, lymph node metastasis, and distant metastasis. Silencing HMGB1 inhibits migration, invasion, and metastasis-related proteins in osteosarcoma cells. Furthermore, the reduced HMGB1 expression in the conditioned media derived from osteosarcoma cells also induces the polarization of M2 TAMs to M1 TAMs. In addition, silencing HMGB1 inhibits the liver and lung metastases of osteosarcoma and reduces the expression of HMGB1, CD163, and CD206 in vivo experiments. HMGB1 regulates macrophage polarization through RAGE. Interestingly, the polarized M2 macrophages could induce osteosarcoma migration and invasion, which in turn results in activation of HMGB1 expression in osteosarcoma cells to form a positive feedback loop. Conclusions HMGB1 and M2 macrophages enhance osteosarcoma migration, invasion, and metastasis capability through positive feedback regulation. These findings reveal the significance of tumor cell and TAM interaction in the metastatic microenvironment.

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Inhibiting HMGB1-RAGE axis prevents pro-inflammatory macrophages/microglia polarization and affords neuroprotection after spinal cord injury

Cited by 141 publications

References 66 publications

Oxidative stress and inflammatory markers in patients with COVID-19: Potential role of RAGE, HMGB1, GFAP and COX-2 in disease severity

Oxidative stress and inflammatory markers in patients with COVID-19: Potential role of RAGE, HMGB1, GFAP and COX-2 in disease severity

Melatonin and Microglia

Positive feedback loop of HMGB1 and tumor-associated macrophages plays a key role in osteosarcoma metastasis

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