Expression of Concern: <scp>HMGB</scp>1 mediates splenomegaly and expansion of splenic <scp>CD</scp>11b+ <scp>L</scp>y‐6<scp>C</scp><sup>high</sup> inflammatory monocytes in murine sepsis survivors

Valdés‐Ferrer, Sergio Iván; Rosas-Ballina, Mauricio; Olofsson, Peder S.; Lü, Ben; Dancho, Meghan; Ochani, Mahendar; Li, Jian Hua; Scheinerman, Joshua A.; Katz, David A.; Levine, Yaakov A.; Hudson, LaQueta; Yang, Huan; Pavlov, Valentin A.; Roth, Jesse; Blanc, Lionel; Antoine, Daniel J.; Chavan, Sangeeta S.; Andersson, Ulf; Diamond, Betty; Tracey, Kevin J.

doi:10.1111/joim.12104

Cited by 65 publications

(53 citation statements)

References 29 publications

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“…Therefore, because of high levels of HMGB1 locally, the dose of mAb 2G7 used here may have been insufficient to neutralize HMGB1 completely. Although we cannot exclude this possibility, previous studies in BXSB lupus mice and a sepsis model have clearly shown a positive effect of anti-HMGB1 antibody treatment, despite the development of splenomegaly (21,36).…”

mentioning

confidence: 83%

“…This antibody has been extensively characterized previously with respect to its HMGB1 neutralizing activity in in vitro and in vivo studies. The neutralizing activity of anti-HMGB1 monoclonal antibody (mAb) has been tested in cell culture assays, with both human and mouse macrophages, and in animal models of HMGB1-mediated damage, such as sepsis (8,(19)(20)(21)(22)(23)(24). Moreover, anti-HMGB1 mAb 2G7 has been shown to neutralize the cytokine isoform of HMGB1 (19).…”

Section: Neutralizing Anti-hmgb1 Antibodymentioning

confidence: 99%

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Treatment with Anti-HMGB1 Monoclonal Antibody Does Not Affect Lupus Nephritis in MRL/lpr Mice

Schaper

Timmeren

Petersen

et al. 2016

Mol Med

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High mobility group box 1 (HMGB1) is a nuclear DNA binding protein that acts as an alarmin when secreted. HMGB1 is increased in systemic lupus erythematosus and might represent a potential therapeutic target. We investigated whether treatment with an anti-HMGB1 antibody affects the development of lupus nephritis in MRL/lpr mice. Seven-week-old MRL/lpr mice were injected intraperitoneally twice weekly for 10 wks with 50 μg monoclonal anti-HMGB1 (2G7, mouse IgG2b) (n = 12) or control antibody (n = 11). Control MRL/MPJ mice (n = 10) were left untreated. Every 2 wks, blood was drawn and urine was collected at wk 7, 11 and 17. Mice were sacrificed at 17 wks for complete disease evaluation. Plasma HMGB1 and anti-HMGB1 levels were increased in MRL/lpr mice compared with control MRL/MPJ mice. There were no differences in albuminuria, urine HMGB1 and plasma levels of complement C3, anti-dsDNA and proinflammatory cytokines between untreated and treated mice at any time point. Lupus nephritis of mice treated with anti-HMGB1 monoclonal antibody (mAb) was classified as class III (n = 3) and class IV (n = 9), while mice treated with control mAb were classified as class II (n = 4), class III (n = 2) and class IV (n = 5). IgG and C3 deposits in kidneys were similar in mice treated with anti-HMGB1 mAb or control mAb. In conclusion, treatment with monoclonal anti-HMGB-1 antibody 2G7 does not affect development of lupus nephritis, disease progression or proinflammatory cytokine levels in MRL/lpr mice. This result indicates that blocking of HMGB1 by this neutralizing antibody does not affect lupus nephritis in MRL/lpr mice.

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mentioning

confidence: 83%

Section: Neutralizing Anti-hmgb1 Antibodymentioning

confidence: 99%

Treatment with Anti-HMGB1 Monoclonal Antibody Does Not Affect Lupus Nephritis in MRL/lpr Mice

Schaper

Timmeren

Petersen

et al. 2016

Mol Med

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“…Disulfide HMGB1 binds to the cell sur face receptor complex MD2TLR4 (12) to enhance release of TNF and IL6, cytokines that have been implicated in the onset of anemia of inflammation in sepsis and negatively regulate erythro poiesis (13,14). We recently identified HMGB1 as a mediator of persistent mor bidity and mortality in sepsis survivors (15,16). Here we show that HMGB1 is both necessary and sufficient to induce anemia in murine sepsis survivors and that HMGB1 is a therapeutic target.…”

Section: Complete Blood Countsmentioning

confidence: 99%

“…The mono clonal antibody detects an epitope in sequence 46-63 of the box A domain, more specifically around glycine in position 58, since this is the single discriminating residue between HMGB1 and HMGB2 in this sequence. On d 9-11 after surgery, CLP survivors received intraperitoneal injections of either antiHMGB1 mono clonal antibody (50 μg/day in 200 μL PBS) or mouse IgG2b (ESMD Chemicals) as isotype control (15). Specificity of 2G7 has been previously demonstrated (15,16).…”

Section: Administration Of Anti-hmgb1 Neutralizing Monoclonal Antibodymentioning

confidence: 99%

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HMGB1 Mediates Anemia of Inflammation in Murine Sepsis Survivors

Valdés‐Ferrer

Papoin

Dancho

et al. 2015

Mol Med

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Patients surviving sepsis develop anemia, but the molecular mechanism is unknown. Here we observed that mice surviving polymicrobial gram-negative sepsis develop hypochromic, microcytic anemia with reticulocytosis. The bone marrow of sepsis survivors accumulates polychromatophilic and orthochromatic erythroblasts. Compensatory extramedullary erythropoiesis in the spleen is defective during terminal differentiation. Circulating tumor necrosis factor (TNF) and interleukin (IL)-6 are elevated for 5 d after the onset of sepsis, and serum high-mobility group box 1 (HMGB1) levels are increased from d 7 until at least d 28. Administration of recombinant HMGB1 to healthy mice mediates anemia with extramedullary erythropoiesis and significantly elevated reticulocyte counts. Moreover, administration of anti-HMGB1 monoclonal antibodies after sepsis significantly ameliorates the development of anemia (hematocrit 48.5 ± 9.0% versus 37.4 ± 6.1%, p < 0.01; hemoglobin 14.0 ± 1.7 versus 11.7 ± 1.2 g/dL, p < 0.01). Together, these results indicate that HMGB1 mediates anemia by interfering with erythropoiesis, suggesting a potential therapeutic strategy for anemia in sepsis. Online address: http://www.molmed.org doi: 10.2119/molmed.2015.00243 † LB and KJT contributed equally to this study. Address correspondence to Lionel Blanc, Laboratory of Developmental Erythropoiesis, TheFeinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY 11030. Phone: 516-562-1507; Fax: 516-562-1599; E-mail: Lblanc@northwell.edu; or Sergio Iván Valdés-Ferrer, Diseases, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Avenida Vasco de Quiroga No.15, Colonia Belisario Domínguez Sección XVI, México, DF, C.P.14080. Phone: +52-55-5487-0900, ext. 4177; Fax: +52-55-5655-6138; E-mail: sergio.valdesf@incmnsz.mx. Submitted November 26, 2015; Accepted for publication December 29, 2015; Published Online (www.molmed.org) December 29, 2015. Laboratory of Neurobiology of Systemic Illness, Departments of Neurology and Infectious H M G B 1 I N A N E M I A O F I N F L A M M A T I O N

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Roles of programmed death‐1 and muscle innate lymphoid cell‐derived interleukin 13 in sepsis‐induced intensive care unit‐acquired weakness

Akama,

Park,

Satoh‐Takayama

et al. 2024

J cachexia sarcopenia muscle

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BackgroundIntensive care unit‐acquired weakness (ICU‐AW) is a syndrome characterized by a long‐term muscle weakness often observed in sepsis‐surviving patients during the chronic phase. Although ICU‐AW is independently associated with increased mortality, effective therapies have yet to be established. Programmed death‐1 (PD‐1) inhibitors have attracted attention as potential treatments for reversing immune exhaustion in sepsis; however, its impact on ICU‐AW remains to be elucidated. Here, we study how PD‐1 deficiency affects sepsis‐induced skeletal muscle dysfunction in a preclinical sepsis model.MethodsChronic sepsis model was developed by treating wild‐type (WT) and PD‐1 knockout (KO) mice with caecal slurry, followed by resuscitation with antibiotics and saline. Mice were euthanized on days 15–17. Body weights, muscle weights, and limb muscle strengths were measured. Interleukin 13 (IL‐13) and PD‐1 expressions were examined by flow cytometry. Messenger RNA (mRNA) expressions of slow‐twitch muscles were measured by reverse transcription and quantitative polymerase chain reaction (RT‐qPCR). In an in vitro study, C2C12 myotubes were treated with lipopolysaccharide (LPS) and recombinant IL‐13 followed by gene expression measurements.ResultsWT septic mice exhibited decreased muscle weight (quadriceps, P < 0.01; gastrocnemius, P < 0.05; and tibialis anterior, P < 0.01) and long‐term muscle weakness (P < 0.0001), whereas PD‐1 KO septic mice did not exhibit any reduction in muscle weights and strengths. Slow‐twitch specific mRNAs, including myoglobin (Mb), troponin I type 1 (Tnni1), and myosin heavy chain 7 (Myh7) were decreased in WT skeletal muscle (Mb, P < 0.0001; Tnni1, P < 0.05; and Myh7, P < 0.05) after sepsis induction, but mRNA expressions of Tnni1 and Myh7 were increased in PD‐1 KO septic mice (Mb, not significant; Tnni1, P < 0.0001; and Myh7, P < 0.05). Treatment of C2C12 myotube cells with LPS decreased the expression of slow‐twitch mRNAs, which was restored by IL‐13 (Mb, P < 0.0001; Tnni1, P < 0.001; and Myh7, P < 0.05). IL‐13 production was significantly higher in ILC2s compared to T cells in skeletal muscle (P < 0.05). IL‐13‐producing ILC2s in skeletal muscle were examined and found to increase in PD‐1 KO septic mice, compared with WT septic mice (P < 0.05). ILC2‐derived IL‐13 was increased by PD‐1 KO septic mice and thought to protect the muscles from experimental ICU‐AW.ConclusionsLong‐term muscle weakness in experimental ICU‐AW was ameliorated in PD‐1 KO mice. ILC2‐derived IL‐13 production in skeletal muscles was increased in PD‐1 KO mice, thereby suggesting that IL‐13 alleviates muscle weakness during sepsis. This study demonstrates the effects of PD‐1 blockade in preserving muscle strength during sepsis through an increase in ILC2‐derived IL‐13 and may be an attractive therapeutic target for sepsis‐induced ICU‐AW.

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Expression of Concern: HMGB1 mediates splenomegaly and expansion of splenic CD11b+ Ly‐6C^high inflammatory monocytes in murine sepsis survivors

Cited by 65 publications

References 29 publications

Treatment with Anti-HMGB1 Monoclonal Antibody Does Not Affect Lupus Nephritis in MRL/lpr Mice

Treatment with Anti-HMGB1 Monoclonal Antibody Does Not Affect Lupus Nephritis in MRL/lpr Mice

HMGB1 Mediates Anemia of Inflammation in Murine Sepsis Survivors

Roles of programmed death‐1 and muscle innate lymphoid cell‐derived interleukin 13 in sepsis‐induced intensive care unit‐acquired weakness

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Expression of Concern: HMGB1 mediates splenomegaly and expansion of splenic CD11b+ Ly‐6Chigh inflammatory monocytes in murine sepsis survivors

Cited by 65 publications

References 29 publications

Treatment with Anti-HMGB1 Monoclonal Antibody Does Not Affect Lupus Nephritis in MRL/lpr Mice

Treatment with Anti-HMGB1 Monoclonal Antibody Does Not Affect Lupus Nephritis in MRL/lpr Mice

HMGB1 Mediates Anemia of Inflammation in Murine Sepsis Survivors

Roles of programmed death‐1 and muscle innate lymphoid cell‐derived interleukin 13 in sepsis‐induced intensive care unit‐acquired weakness

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Expression of Concern: HMGB1 mediates splenomegaly and expansion of splenic CD11b+ Ly‐6C^high inflammatory monocytes in murine sepsis survivors