High mobility group box1 as a danger signal inducing the infiltration of neutrophils and macrophages in thioacetamide-induced rat liver injury

Mizuki Kuramochi; Mohammad Rabiul Karim; Takeshi Izawa; Mitsuru Kuwamura; Jyoji Yamate

doi:10.1293/tox.2024-0055

. 2024 Sep 16;38(1):49–58. doi: 10.1293/tox.2024-0055

High mobility group box1 as a danger signal inducing the infiltration of neutrophils and macrophages in thioacetamide-induced rat liver injury

Mizuki Kuramochi ¹, Mohammad Rabiul Karim ^1,², Takeshi Izawa ¹, Mitsuru Kuwamura ¹, Jyoji Yamate ^1,^*

PMCID: PMC11745500 PMID: 39839722

Abstract

The liver, a major organ involved in substance metabolism, is highly susceptible to toxicity induced by chemicals and their metabolites. Although damage-associated molecular patterns (DAMPs) have been implicated in the development of sterile inflammation following cell injury, their involvement in chemically induced hepatocellular injury remains underexplored. This study aimed to determine the role of high-mobility group box 1 (HMGB1), a DAMP, in a rat model of liver injury treated with thioacetamide, a hepatotoxicant. The rats were administered thioacetamide and treated with HMGB1 neutralizing antibody. Histopathological analysis revealed the absence of significant differences between control rats and HMGB1 neutralizing antibody-treated rats. However, HMGB1 neutralizing antibody-treated rats showed a reduction in the hepatic devitalization enzymes, a decrease in the number of anti-inflammatory cluster of differentiation CD163⁺ M2 macrophages and neutrophils in the injured area, and a decrease in cytokine expression. These results suggest that HMGB1 leads to the progression of inflammation after chemically induced hepatocyte injury and may represent a therapeutic target for mitigating such injury.

Keywords: high mobility group box1, neutrophils, macrophages, thioacetamide, rat

Introduction

When various chemicals in the environment enter the body, most are metabolized in the liver and excreted as non-toxic substances; however, some chemicals or their metabolites can be toxic to cells¹. Hepatotoxic chemicals can be classified into those that directly damage the hepatocytes, those that damage the hepatocytes through their metabolites, and those that cause hepatotoxicity due to their specific properties, such as haptens²^,³^,⁴. Additionally, inflammatory cells that respond to tissue injury, particularly M1 macrophages involved in tissue injury and/or M2 macrophages involved in tissue repair, may influence the severity of hepatotoxicity⁵^,⁶.

Thioacetamide (TAA) is a well-known hepatotoxicant; its metabolites, thioacetamide-sulfoxide (TASO) and thioacetamide S,S-oxide (TASO₂), form adducts with intracellular macromolecules in hepatocytes, resulting in hepatocyte injury due to organelle damage⁷^,⁸^,⁹. Histopathological examinations of TAA-induced liver lesions in rats have demonstrated centrilobular coagulation necrosis with macrophage infiltration¹⁰^,¹¹. In addition, neutrophils infiltrated in the early stages of injury, indicating the crucial role of neutrophils and macrophages in TAA-induced hepatotoxicity¹².

Damage-associated molecular patterns (DAMPs) are recognized as key factors in recruiting inflammatory cells to injured areas and activating innate immunity¹³^,¹⁴. High mobility group box 1 (HMGB1) and S100 proteins are representative of DAMPs¹³^,¹⁵^,¹⁶. Under physiological conditions, molecules belonging to the DAMPs family perform various functions necessary for cellular homeostasis¹⁷. However, when high amounts of DAMPs are released from injured cells, these molecules activate receptor cascades as ligands for innate immune receptors, such as Toll-like receptors¹⁸^,¹⁹^,²⁰^,²¹. In this study, we investigated the expression status of macrophages, neutrophils, and cytokines in TAA-induced acute liver injury following pretreatment with an HMGB1 neutralizing antibody. Pretreatment with HMGB1 neutralizing antibody led to a reduction in the serum levels of hepatic devitalization enzymes and the number of anti-inflammatory cluster of differentiation (CD) 163⁺ M2 macrophages and neutrophils in the injured area, with a decrease in cytokine expression levels, reducing the likelihood of TAA-induced liver injury.

Materials and Methods

Animals and experimental procedures

Thirty-two 5-week-old male F344/DuCrlCrlj rats were obtained from the Jackson Laboratory (Yokohama, Kanagawa, Japan). The rats were maintained in a room under a controlled environment at 21 ± 3°C with a 12-h light-dark cycle; they were fed a standard rodent chow (DC-8, CLEA Japan, Tokyo, Japan) and supplied with tap water ad libitum. After 1 week of acclimatization, the rats were randomly divided into four groups: 1) saline injection with control IgY post-treatment (saline+IgY group, 16 rats), 2) saline injection with αHMGB1 post-treatment (saline+αHMGB1 group, 16 rats), 3) TAA injection with control IgY post-treatment (TAA+IgY group,16 rats), and 4) TAA injection with αHMGB1 post-treatment (TAA+αHMGB1 group, 16 rats). The TAA-injected groups received intraperitoneal injections of TAA dissolved in saline (50 mg/kg body weight: Wako Pure Chemicals, Osaka, Japan). A dose of 50 mg/kg body weight was selected based on the results of preliminary studies, which reported that a dose of more than 100 mg/kg body weight caused severe liver injury in rats, complicating the assessment of αHMGB1’s specific effects. Equal volumes of saline were administered to the control groups (saline + IgY and saline + HMGB1). At 6 h after TAA injection, the rats were injected with an HMGB1 neutralizing antibody derived from chickens (αHMGB1; 300 μg/rat; Shino-Test, Tokyo, Japan) via the tail vein. The neutralizing antibody dose was determined according to the manufacturer’s recommendations. The IgY-injected rats were administered an equal volume of normal chicken IgY (Shino-Test). The biological efficacy of this neutralizing antibody has been demonstrated in previous studies²²^,²³^,²⁴. The rats were euthanized under deep isoflurane anesthesia, and whole blood was collected from the abdominal artery and liver at 0, 12, 18, and 24 h after TAA administration (n=4 in each group); the livers of rats at 0 h were used as controls. The levels of serum aspartate transaminase (AST) and alanine transaminase (ALT) were measured by SRL Inc. (Tokyo, Japan).

All animal experiments were conducted in accordance with the institutional guidelines approved by the ethics committee of Osaka Metropolitan University for Animal Care (no. 29-5).

Histopathology and immunohistochemistry

Tissues from the left lateral lobes of the liver were fixed in a 10% neutral-buffered formalin or periodate-lysine-paraformaldehyde (PLP) solution. Tissues were routinely processed and embedded in paraffin. Deparaffinized sections, cut at 3 μm in thickness, were stained with hematoxylin and eosin (HE) for histopathological examination. Immunohistochemistry was performed as previously described²⁵. PLP-fixed sections were used for immunohistochemistry with rabbit monoclonal antibodies against Iba-1 (for macrophages, 1:500; Wako Pure Chemical Industries, Osaka, Japan), CD68 (clone ED1 for M1 macrophages, 1:500; Serotec, Kidlington, UK), CD163 (clone ED2 for M2 macrophages, 1:500; Serotec), and myeloperoxidase (for neutrophils, 1:500; R&D Systems, Minneapolis, MN, US). After pretreated by microwave for 20 min in 0.01 M citrate buffer (pH 6.0) for Iba-1 and myeloperoxidase, or proteinase K (100 μg/mL) treatment for 10 min for CD68 and CD163, sections were incubated with each primary antibody for 1 h at room temperature, followed by 1-h incubation with peroxidase-conjugated secondary antibody (Histofine Simple Stain MAX-PO; Nichirei, Tokyo, Japan). Positive reactions were detected with 3, 3′-diaminobenzidine (DAB Substrate Kit; Nichirei). Sections were lightly counterstained with hematoxylin.

Cell count

The positive cells reacting to myeloperoxidase, CD68, CD163, and Iba-1 in the affected centrilobular area were counted by randomly selecting three different areas of four different rats using WinROOF (Mitani Corp., Fukui, Japan) and expressed as the number of positive cells per unit area (cells/mm²), as described in our previous studies¹¹^,¹².

Reverse transcriptase polymerase chain reaction

The liver samples were immersed in RNAlater reagent (Qiagen GmbH, Hilden, Germany) overnight at 4°C and stored at −80°C. Total ribonucleic acid (RNA) was extracted using the SV Total RNA Isolation System (Promega, Madison, WI, USA). Two μg of total RNA was reverse-transcribed with SuperScript VILO reverse transcriptase (Life Technologies, Carlsbad, CA, USA). Real-time polymerase chain reaction (PCR) was performed using TaqMan Gene Expression Assays (Life Technologies) on a PikoReal Real-Time 96 PCR System (Thermo Fisher Scientific, Waltham, MA, USA). The TaqMan probes specific for the cytokines were used as follows (assay IDs): mcp-1 (monocyte chemotactic protein (MCP)-1), Rn00580555_m1; il-6 (interleukin (IL)-6), Rn01410330_m1; tgb1 (transforming growth factor-beta 1 (TGF-β1)), Rn01440674_m1; cxcl1 (chemokine (C-X-C motif) ligand 1 (CXCL1)), Rn00578225_m1; and ribosomal 18s (18s), Hs99999901_s1. 18s rRNA was used as a reference gene. The data were analyzed using the 2^−ΔΔC_T method, as described in our previous studies¹¹^,¹².

Statistical analysis

Data were expressed as the mean ± standard deviation. Statistical analysis was performed using the Student’s t-test. A p-value of <0.05 was considered significant.

Results

HMGB1 neutralizing antibody suppressing TAA-induced hepatic injury

Our previous study suggested that HMGB1 translocates from the hepatocellular nucleus to the cytoplasm in rats during TAA-induced acute liver injury¹². Considering that HMGB1 functions as a DAMP that facilitates inflammation during the development of TAA-induced acute hepatocellular injury, we investigated the role of HMGB1 in rats with HMGB1 neutralization after TAA injection. No histopathological changes were observed in the saline+IgY and saline+αHMGB1 groups. Likewise, no significant changes were observed in other parameters (serum hepatic enzymes and results of immunohistochemistry for macrophages and neutrophils) between the saline+IgY and saline+αHMGB1 groups (data not shown). These data indicate that neither IgY nor αHMGB1 treatment alone did not affect liver functions. Therefore, we focused on examining the differences between the TAA+IgY and TAA+αHMGB1 groups.

No histopathological changes were found in the TAA+IgY and TAA+αHMGB1 groups at 0 h after TAA administration (Fig. 1a and 1e). At 12 and 18 h after TAA administration, slight degeneration and hypertrophy of hepatocytes were observed in the centrilobular areas of the TAA+IgY and TAA+αHMGB1 groups (Fig. 1b and 1f). Subsequently, a small to moderate number of inflammatory cells emerged in the sinusoids of the centrilobular areas (Fig. 1c and 1g), primarily consisting of macrophages and neutrophils (as described below). At 24 h after TAA administration, the centrilobular area exhibited more severe degeneration and necrosis of hepatocytes with inflammatory cell infiltration (Fig. 1d and 1h). A detailed comparison of the two experimental groups at each timepoint revealed that the number of degenerative hepatocytes was relatively fewer in the TAA+αHMGB1 group than that in the TAA+IgY group at 18 and 24 h after TAA administration (Table 1; overall evaluation of hepatocyte injury in each group).

Table 1. Grading of Hepatocyte Injury and Inflammation in Thioacetamide-induced Liver Injury with HMGB1 Neutralization (overall evaluation in each group).

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The serum hepatic enzyme levels were measured to assess the degree of hepatocyte injury. No statistical differences were found in the serum AST or ALT values between the TAA+αHMGB1 and TAA+IgY groups at 12 or 18 h after TAA administration, while both values were lower in the TAA+αHMGB1 group than in the TAA+IgY group at 24 h (Fig. 2a and 2b). According to the histopathological findings and the levels of serum hepatic enzymes, HMGB1 neutralizing antibody can suppress TAA-induced acute hepatocellular injury.

Fig. 2. — Hepatic enzyme levels (AST and ALT) in TAA+IgY- and TAA+αHMHG1-treated rats (**a, b**). Although the values are similar at 12 and 18 h, the AST value in TAA+αHMHG1-treated rats is significantly lower than that in the TAA+IgY-treated group. AST: aspartate transaminase; ALT: alanine transaminase. Values are expressed as the mean ± standard deviation. *p<0.05 by the Student’s t-test.

HMGB1 neutralizing antibody reducing the activation of M2 macrophages

The effect of HMGB1 on the appearance of M1 and M2 macrophages was also investigated. Cells reacting to the Iba-1 antibody, a wide-ranging marker of tissue macrophages²⁶, appeared in the injured centrilobular areas at 12 h and became most prominent at 24 h (Fig. 3a). The kinetics at 12 and 18 h were similar between the TAA+IgY and TAA+αHMGB1 groups; however, at 24 h, the number of Iba-1-positive cells in the TAA+αHMGB1 group was significantly lower than that in the TAA+IgY group (Fig. 3b). The expression of MCP-1, a major macrophage chemoattractant factor in the liver⁵, in the TAA+αHMGB1 group was significantly lower than that in the TAA+IgY group at 24 h (Fig. 3c).

Fig. 3. — Immunohistochemistry for macrophages is performed using anti-Iba-1 antibody. (a) Iba-1 positive cells are observed around the centrilobular zone at 24 h after TAA injection. Counterstained with hematoxylin. (b) The number of Iba-1 positive macrophages is significantly reduced in the in TAA+IgY- and TAA+αHMHG1-treated rats at 24 h. (c) The mRNA expression levels of MCP-1 (a factor for macrophage induction) in TAA+IgY- and TAA+αHMHG1-treated rats. The expression level at 24 h is significantly lower in the TAA+αHMHG1-treated rats compared with that in the TAA+IgY-treated rats. Values are expressed as the mean ± standard deviation. CV: central vein; *p<0.05 by the Student’s t-test

Immunohistochemical analysis was performed using CD68 antibody, a marker of M1 macrophages. In the TAA+IgY group, only a few CD68-positive M1 macrophages were observed after 12 h. At 18 h, some positive cells were found in the injured area; at 24 h, a greater number of CD68-positive cells was observed in the injured area (Fig. 4a). In the TAA+αHMGB1 group, only a few positive cells were observed at 12 h; subsequently, the positive cells were more frequently observed at 18 and 24 h. No significant difference was found in the number of CD68-positive M1 macrophages at any time point (Fig. 4b). The gene expression of IL-6, a pro-inflammatory cytokine, was significantly lower in the TAA+αHMGB1 group compared with that in the TAA+IgY group at 12 and 24 h (Fig. 4c).

Fig. 4. — Immunohistochemistry for M1 macrophages is performed using anti-CD68 antibody. (a) M1 macrophages are observed around the centrilobular areas at 24 h after TAA injection. Counterstained with hematoxylin. (b) The numbers of CD68-positive macrophages in TAA+IgY- and TAA+αHMHG1-treated rats. No statistical difference in the number between the TAA+IgY- and TAA+αHMHG1-treated rats. (c) The mRNA expression of IL-6 (a factor of M1 macrophages) in TAA+IgY- and TAA+αHMHG1-treated treated rats. The expression is significantly lower at 12 and 24 h in TAA+αHMHG1-treated rats compared with that in TAA+IgY-treated rats. Values are expressed as the mean ± standard deviation. CV: central vein; *p<0.05 by Student’s t-test.

Immunohistochemistry using the CD163 antibody, a marker of M2 macrophages, was performed. In the TAA+αHMGB1 and TAA+IgY groups, Kupffer cells along the sinusoids reacted to CD163, in contrast to untreated controls, indicating activation following TAA injection²⁷. In addition to the Kupffer cells, M2 macrophages reacting to CD163 were noted in the affected centrilobular areas of the TAA+IgY (Fig. 5a–5c) and TAA+αHMGB1 (Fig. 5d–5f) groups, showing large-round or stellate-shaped configuration. The number of CD163-positive cells at 12, 18, and 24 h was significantly lower in the TAA+αHMGB1 group compared with that in the TAA+IgY group (Fig. 5g). However, the gene expression of TGF-β1, as an anti-inflammatory cytokine associated with M2 macrophages, tended to decrease in the TAA+αHMGB1 group at each time point compared with that in the TAA+IgY group, although no significant differences were found (Fig. 5h).

Fig. 5. — Quantitative analysis of M2 macrophages using CD163 antibody (for M2 macrophages). (**a–c**) The expression of CD163-positive macrophages in the centrilobular injured areas of TAA+IgY-treated rats increased at 12, 18, and 24 h. (**d–f**) In TAA+αHMHG1-treated rats, the expression of CD163-positive macrophages show a similar pattern to those seen in TAA+IgY-treated rats at 12, 18, and 24 h. (g) The number of CD163-positive macrophages significantly reduced at 12, 18, and 24 h in TAA+αHMHG1-treated rats compared with that in TAA+IgY-treated rats. (h) The mRNA expression of TGF-β1 (a factor for M2 macrophages) in TAA+IgY- and TAA+αHMHG1-treated rats. The expression show a tendency to decrease at each timepoint in TAA+αHMHG1-treated rats compared with that in TAA+IgY-treated rats. Counterstained with hematoxylin. CV: central vein. The values are expressed as the mean ± standard deviation. *p<0.05 by Student’s t-test

HMGB1 neutralizing antibody suppressing neutrophils during the early stages of inflammation

In the TAA+IgY group, myeloperoxidase-positive neutrophils were scattered after 12 h (Fig. 6a). At 18 h, positive cells aggregated in the affected centrilobular areas (Fig. 6b). The number of neutrophils was higher at 24 h, forming clusters in the affected areas (Fig. 6c). The TAA+αHMGB1 group showed a noticeably lower number of neutrophils at 12 h compared with the TAA+IgY group (Fig. 6d). At 18 h (Fig. 6e) and 24 h (Fig. 6f), the numbers of neutrophils in the TAA+αHMGB1 group appeared to be lower than those in the TAA+IgY group, although no significant differences were found in these numbers between the groups (Fig. 6g). Notably, the gene expression level of CXCL1, a chemokine involved in neutrophil mobilization and activation²⁸, was significantly lower at 12 h in the TAA+αHMGB1 group compared with that in the TAA+IgY group; furthermore, the TAA+αHMGB1 group at 18 and 24 h tended to have lower CXCL1 levels compared with the TAA+IgY group (Fig. 6h). These results indicate that neutrophil infiltration, particularly in the early stages, is suppressed by the neutralization of HMGB1.

Discussion

In tissue injury caused by bacterial or viral infection, the pathogen is recognized as an antigen and induces immune responses, such as phagocytosis by macrophages/NK cells and antibody production by B cells, as part of innate or acquired immunity²⁸^,²⁹. However, chemical substances can also elicit immune responses even if they are not recognized as antigens¹⁷. In the absence of antigens, DAMPs play an important role as triggers of inflammation¹³^,¹⁵^,¹⁶. Among DAMPs, HMGB1 is regarded as an important factor in tissue injury in animal models of ischemia-reperfusion³⁰^,³¹^,³². However, the roles of HMGB1 in hepatotoxicity remain unclear.

After TAA injection (50 mg/kg body weight), as reported in our previous study¹², slight hepatocyte degeneration in the centrilobular areas was observed at 12 h. At 18 h, this degeneration was accompanied by the production of a small number of inflammatory cells. At 24 h, these findings became more pronounced, showing coagulation necrosis of hepatocytes. This study analyzed the association of HMGB1 with inflammatory cells during the early stages of TAA-induced liver lesions.

In the present HMGB1 neutralization study, at 24 h, when histopathological changes such as coagulation necrosis with inflammatory cell reaction were most prominent, the AST and ALT values significantly decreased in the TAA+αHMGB1 group. Additionally, the expression of Iba-1-positive macrophages and its chemoattractant factor (MCP-1) significantly decreased in the TAA+αHMGB1 group at this time point. The Iba-1 antibody was used to detect all types of macrophages, including M1 and M2 macrophages⁴¹. In addition to the differences in histopathological findings between the TAA+IgY and TAA+αHMGB1 groups, reductions in AST/ALT values, Iba-1-positive macrophage number, and MCP-1 expression may suggest an improvement in TAA-induced liver failure in the TAA+αHMGB1 group. As shown in our previous study¹², after TAA injection, HMGB1 translocated from the nucleus into the cytoplasm in hepatocytes. It may have been released from injured hepatocytes, thereby leading to inflammation in the affected centrilobular area. HMGB1 influences the infiltration of inflammatory cells in the ischemia-reperfusion animal models³⁰^,³¹. The reduction in Iba-1-positive macrophage expression in conjunction with decreased MCP-1 expression may result from treatment with αHMGB1.

M1 and M2 macrophages play important roles in the pathogenesis of hepatotoxicity²⁶^,³³^,³⁴. The inflammatory cells in TAA-induced rat liver lesions primarily consist of M1 and M2 macrophages, with the M1 type inducing inflammatory reactions with tissue injury. Meanwhile, the M2 type contributes to the resolution of inflammatory reactions³⁵. Although no significant changes were observed in the appearance of CD68-expressing M1 macrophages at each time point (12, 18, and 24 h) between the TAA+IgY and TAA+αHMGB1 groups, IL-6 expression was significantly decreased at 24 h in the TAA+αHMGB1 group. As IL-6 is primarily produced by M1 macrophages, its increased expression indicates tissue injury with activated inflammation¹⁷. Furthermore, the expression of CD163-expressing M2 macrophages significantly decreased at each time point (12, 18, and 24 h) in the TAA+αHMGB1 group. TGF-β1, an anti-inflammatory factor produced mainly by M2 macrophages, tended to decrease at each time point as the number of M2 macrophages decreased. Previous studies have shown that the reduction in the number of macrophages by pretreatment with gadolinium chloride improved TAA-induced rat hepatic lesions³⁶. Conversely, dexamethasone pretreatment suppressed TAA-induced hepatocyte injury and subsequent fibrosis by decreasing the numbers of M1 and M2 macrophages³⁴. These findings suggest that treatment with αHMGB1 may have suppressed the expression of macrophages (particularly M2 macrophages) and their-related factors, thereby improving TAA-induced liver failure.

Previously, we reported that the injection of TAA at 50 mg/kg body weight in rats induced liver lesions, characterized by the presence of macrophages and neutrophils at the early stages¹². Neutrophils are known to participate in liver lesions induced by halothane³⁷ and acetaminophen³⁸^,³⁹ in experimental animals. In the present study, myeloperoxidase-positive neutrophils were observed at 12, 18, and 24 h after TAA injection, with a time-dependent increase in the TAA+IgY and TAA+αHMGB1 groups. Notably, the number of neutrophils at 12 h was significantly decreased in the TAA+αHMGB1 group compared with that in the TAA+IgY group. Concurrently, CXCL1, a factor that induces and activates neutrophils⁴⁰, was significantly decreased in the TAA+αHMGB1 group at 12 h. These findings indicated that αHMGB1 treatment effectively suppressed the infiltration of neutrophils, suggesting that neutrophils play an important role in the early stages of TAA-induced hepatotoxicity. In addition to TAA-induced hepatotoxicity, neutrophils were observed as inflammatory cells after ischemia treatment in ischemia-reperfusion experiments involving the brain and liver of rats and mice³⁰^,³¹.

In conclusion, the present study using the αHMGB1 showed that HMGB1 may act as a trigger for inflammation in TAA-induced rat liver lesions, particularly affecting neutrophils and M2 macrophages. The neutralization of HMGB1 might improve liver injury by decreasing the number of inflammatory cells. HMGB1 released at the early stages may contribute to the development of liver lesions induced by acetaminophen³⁸^,³⁹ and methimazole in mice and rats⁴¹. Recently, HMGB1 has been identified as a factor in human autoimmune diseases such as lupus erythematosus and Sjogren’s syndrome⁴², as well as in the development of Alzheimer’s disease⁴³. HMGB1 levels are elevated in the cerebrospinal fluid of dogs with encephalitis⁴⁴ and may correlate with the prognosis of canine acute pancreatitis⁴⁵. In addition to the role of HMGB1 as a possible biomarker, the present study provides valuable insights into the pathogenesis of hepatotoxicity and enhances understanding of the HMGB1’s involvement in human and animal diseases.

Declaration of Potential Conflicts of Interests

The authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Acknowledgments

This work was supported in part by JSPS KAKENHI (grant number: 18J14823, (to Kuramochi)) and JSPS KAKENHI (grant number: 19H03130 (to Yamate) and the Grant for Advanced Research in Education, Bangladesh Bureau of Educational Information & Statistics, Ministry of Education (grant number: SD20211598 (to Karim)).

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43.Fujita K, Motoki K, Tagawa K, Chen X, Hama H, Nakajima K, Homma H, Tamura T, Watanabe H, Katsuno M, Matsumi C, Kajikawa M, Saito T, Saido T, Sobue G, Miyawaki A, and Okazawa H. HMGB1, a pathogenic molecule that induces neurite degeneration via TLR4-MARCKS, is a potential therapeutic target for Alzheimer’s disease. Sci Rep. 6: 31895. 2016. [DOI] [PMC free article] [PubMed] [Google Scholar]
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[r40] 40.Sawant KV, Xu R, Cox R, Hawkins H, Sbrana E, Kolli D, Garofalo RP, and Rajarathnam K. Chemokine CXCL1-mediated neutrophil trafficking in the lung: role of CXCR2 activation. J Innate Immun. 7: 647–658. 2015. [DOI] [PMC free article] [PubMed] [Google Scholar]

[r41] 41.Akai S, Uematsu Y, Tsuneyama K, Oda S, and Yokoi T. Kupffer cell-mediated exacerbation of methimazole-induced acute liver injury in rats. J Appl Toxicol. 36: 702–715. 2016. [DOI] [PubMed] [Google Scholar]

[r42] 42.Magna M, and Pisetsky DS. The role of HMGB1 in the pathogenesis of inflammatory and autoimmune diseases. Mol Med. 20: 138–146. 2014. [DOI] [PMC free article] [PubMed] [Google Scholar]

[r43] 43.Fujita K, Motoki K, Tagawa K, Chen X, Hama H, Nakajima K, Homma H, Tamura T, Watanabe H, Katsuno M, Matsumi C, Kajikawa M, Saito T, Saido T, Sobue G, Miyawaki A, and Okazawa H. HMGB1, a pathogenic molecule that induces neurite degeneration via TLR4-MARCKS, is a potential therapeutic target for Alzheimer’s disease. Sci Rep. 6: 31895. 2016. [DOI] [PMC free article] [PubMed] [Google Scholar]

[r44] 44.Miyasho T, Nakamura K, Nomura S, Kawasako K, Nakade T, Yamada S, and Yokota H. High mobility group box 1 (HMGB1) protein is present in the cerebrospinal fluid of dogs with encephalitis. J Vet Med Sci. 73: 917–922. 2011. [DOI] [PubMed] [Google Scholar]

[r45] 45.Lee JH, Song WJ, An JH, Chae HK, Park SM, Li Q, and Youn HY. Role of serum high-motility group box-1 (HMGB1) concentration as a prognostic factor in canine acute pancreatitis: a pilot study. Res Vet Sci. 141: 26–32. 2021. [DOI] [PubMed] [Google Scholar]

PERMALINK

High mobility group box1 as a danger signal inducing the infiltration of neutrophils and macrophages in thioacetamide-induced rat liver injury

Mizuki Kuramochi

Mohammad Rabiul Karim

Takeshi Izawa

Mitsuru Kuwamura

Jyoji Yamate

Abstract

Introduction