Naringin Decreases TNF-α and HMGB1 Release from LPS-Stimulated Macrophages and Improves Survival in a CLP-Induced Sepsis Mice

Gil, Minchan; Kim, Yun Kyu; Hong, Sang Bum; Lee, Kyung Jin

doi:10.1371/journal.pone.0164186

Cited by 53 publications

(30 citation statements)

References 37 publications

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“…The protective effects of rPPE18 were, therefore, demonstrated in two models of sepsis. Ability to reduce TNF-a and attenuate organ damage in CLP-induced sepsis correlates with increased survival as has been demonstrated previously (13,14,(70)(71)(72). rPPE18 was able to consistently reduce elevated levels of TNF-a in E. coli BL21induced and CLP-induced sepsis when administered therapeutically.…”

Section: Discussionsupporting

confidence: 75%

“…In patients with severe sepsis, anti-TNF-a Ab reduced mortality and in patients suffering from shock, there was a trend for better survival with use of anti-TNF-a Ab (12). Also, reduction in levels of TNF-a and overall inflammation correlates with increased survival in animal models of sepsis (13)(14)(15). Indeed, an exaggerated and dysregulated inflammatory response poses a challenge in sepsis and efforts need to be geared toward identifying effective anti-inflammatory agents which can reduce TNF-a and inflammation for successful resolution of sepsis (16)(17)(18)(19)(20).…”

mentioning

confidence: 99%

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Mycobacterium tuberculosis PPE18 Protein Reduces Inflammation and Increases Survival in Animal Model of Sepsis

Ahmed

Dolasia

Mukhopadhyay

2018

The Journal of Immunology

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PPE18 is a member of the PPE family. Previous studies have shown that recombinant PPE18 (rPPE18) protein binds to TLR2 and triggers a signaling cascade which reduces levels of TNF-α and IL-12, and increases IL-10 in macrophages. Because TNF-α is a major mediator of the pathophysiology of sepsis and blocking inflammation is a possible line of therapy in such circumstances, we tested the efficacy of rPPE18 in reducing symptoms of sepsis in a mouse model of induced septic peritonitis. rPPE18 significantly decreased levels of serum TNF-α, IL-1β, IL-6, and IL-12 and reduced organ damage in mice injected i.p. with high doses of Peritoneal cells isolated from rPPE18-treated mice had characteristics of M2 macrophages which are protective in excessive inflammation. Additionally, rPPE18 inhibited disseminated intravascular coagulation, which can cause organ damage resulting in death. rPPE18 was able to reduce sepsis-induced mortality when given prophylactically or therapeutically. Additionally, in a mouse model of cecal ligation and puncture-induced sepsis, rPPE18 reduced TNF-α, alanine transaminase, and creatinine, attenuated organ damage, prevented depletion of monocytes and lymphocytes, and improved survival. Our studies show that rPPE18 has potent anti-inflammatory properties and can serve as a novel therapeutic to control sepsis.

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Section: Discussionsupporting

confidence: 75%

mentioning

confidence: 99%

Mycobacterium tuberculosis PPE18 Protein Reduces Inflammation and Increases Survival in Animal Model of Sepsis

Ahmed

Dolasia

Mukhopadhyay

2018

The Journal of Immunology

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“…A number of studies have demonstrated that HMGB1 serves a critical role in the initiation of an inflammatory signaling cascade in sepsis, and that it is the most important pro-inflammatory cytokine of the lethal effect of sepsis ( 21 ). Compared with inflammatory cytokines involved in early sepsis, including TNF-α, HMGB1 is characterized by late elevated expression for a prolonged duration, providing a wide window of time for the clinical treatment of sepsis ( 22 ). As an innate immune cell, macrophages serve a crucial role in fighting against pathogenic microorganisms and initiating an immune response ( 23 ).…”

Section: Discussionmentioning

confidence: 99%

Inhibitory effects of miR‑25 targeting HMGB1 on macrophage secretion of inflammatory cytokines in sepsis

2018

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High mobility group box 1 (HMGB1) can promote the migration of macrophages and the release of inflammatory cytokines, functions associated with the occurrence of sepsis. The role of microRNA (miR)-25 in the targeted regulation of HMGB1 expression and the release of macrophage inflammatory cytokines remains uncharacterized. The present study investigated the association between miR-25, HMGB1 and sepsis by analyzing the expression of miR-25 and HMGB1 in patients with sepsis. The present study also investigated whether miR-25 serves a role in targeting the regulation of HMGB1 expression and macrophage inflammatory factor release. Patients with sepsis were selected from the Intensive Care Unit, and serum levels of HMGB1. The expression of miR-25 and HMGB1 in serum and peripheral blood mononuclear cells (PBMCs) was compared. Macrophages were cultured in vitro and divided into 5 groups following treatment with lipopolysaccharide (LPS). The expression levels of miR-25, HMGB1, phosphorylated (p-)p65, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and HMGB-1 were compared, and the migration ability of cells was investigated by Transwell assays. Compared with the healthy controls, patients with sepsis exhibited elevated expression of HMGB1 and decreased expression of miR-25 in serum and PBMCs. Following treatment with LPS, the expression of HMGB1 and p-p65 was elevated, and the expression of miR-25 was decreased in macrophages compared with untreated cells. Following transfection with miR-25 mimics and/or short interfering RNA-HMGB1, the expression of HMGB1 in macrophages decreased significantly, the expression of p-p65, HMGB-1, TNF-α and IL-6 in the culture solution were also decreased, and the migration ability of macrophages was attenuated. The present study suggests that miR-25 attenuated the induction of HMGB1 by LPS, decreased the activity of nuclear factor-κB and the transcriptional activation of TNF-α and IL-6, and suppressed the migration of macrophages. Inhibiting expression of miR-25 may serve a role in upregulating HMGB1 expression, promoting the secretion of inflammatory cytokines and resulting in sepsis.

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“…HMGB1 can reach the extracellular space, once released by necrotic epithelial cells and exerts its DAMPs function or when secreted by activated innate immune cells, where it mediates potent inflammatory effects. 10,13 Macrophages and other innate immune cells actively secrete HMGB1 upon an inflammatory challenge (interleukin 1β [IL1β], lipopolysaccharide [LPS], or tumor necrosis factor α [TNFα]) in vitro and in vivo [14][15][16][17] supporting a possible role of macrophage-derived HMGB1 in tissue scarring. Recent publications documented a critical role of extracellular HMGB1 in regeneration and tissue repair processes in bone, muscle, or liver 18-21 suggesting a potential role in tissue fibrogenesis.…”

Section: Introductionmentioning

confidence: 99%

Macrophage‐derived HMGB1 is dispensable for tissue fibrogenesis

et al. 2019

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Alarmins and damage‐associated molecular patterns (DAMPs) are powerful inflammatory mediators, capable of initiating and maintaining sterile inflammation during acute or chronic tissue injury. Recent evidence suggests that alarmins/DAMPs may also trigger tissue regeneration and repair, suggesting a potential contribution to tissue fibrogenesis. High mobility group B1 (HMGB1), a bona fide alarmin/DAMP, may be released passively by necrotic cells or actively secreted by innate immune cells. Macrophages can release large amounts of HMGB1 and play a key role in wound healing and regeneration processes. Here, we hypothesized that macrophages may be a key source of HMGB1 and thereby contribute to wound healing and fibrogenesis. Surprisingly, cell‐specific deletion approaches, demonstrated that macrophage‐derived HMGB1 is not involved in tissue fibrogenesis in multiple organs with different underlying pathologies. Compared to control HMGB1Flox mice, mice with macrophage‐specific HMGB1 deletion (HMGB1ΔMac) do not display any modification of fibrogenesis in the liver after CCL4 or thioacetamide treatment and bile duct ligation; in the kidney following unilateral ureter obstruction; and in the heart after transverse aortic constriction. Of note, even under thermoneutral housing, known to exacerbate inflammation and fibrosis features, HMGB1ΔMac mice do not show impairment of fibrogenesis. In conclusion, our study clearly establishes that macrophage‐derived HMGB1 does not contribute to tissue repair and fibrogenesis.

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Naringin Decreases TNF-α and HMGB1 Release from LPS-Stimulated Macrophages and Improves Survival in a CLP-Induced Sepsis Mice

Cited by 53 publications

References 37 publications

Mycobacterium tuberculosis PPE18 Protein Reduces Inflammation and Increases Survival in Animal Model of Sepsis

Mycobacterium tuberculosis PPE18 Protein Reduces Inflammation and Increases Survival in Animal Model of Sepsis

Inhibitory effects of miR‑25 targeting HMGB1 on macrophage secretion of inflammatory cytokines in sepsis

Macrophage‐derived HMGB1 is dispensable for tissue fibrogenesis

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