Publications by authors named "Ulf Andersson"

116 Publications

HMGB1 released from nociceptors mediates inflammation.

Proc Natl Acad Sci U S A 2021 Aug;118(33)

Laboratory of Biomedical Sciences, Institute of Bioelectronic Medicine, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY 11030;

Inflammation, the body's primary defensive response system to injury and infection, is triggered by molecular signatures of microbes and tissue injury. These molecules also stimulate specialized sensory neurons, termed nociceptors. Activation of nociceptors mediates inflammation through antidromic release of neuropeptides into infected or injured tissue, producing neurogenic inflammation. Because HMGB1 is an important inflammatory mediator that is synthesized by neurons, we reasoned nociceptor release of HMGB1 might be a component of the neuroinflammatory response. In support of this possibility, we show here that transgenic nociceptors expressing channelrhodopsin-2 (ChR2) directly release HMGB1 in response to light stimulation. Additionally, HMGB1 expression in neurons was silenced by crossing synapsin-Cre (Syn-Cre) mice with floxed HMGB1 mice (HMGB1). When these mice undergo sciatic nerve injury to activate neurogenic inflammation, they are protected from the development of cutaneous inflammation and allodynia as compared to wild-type controls. Syn-Cre/HMGB1 mice subjected to experimental collagen antibody-induced arthritis, a disease model in which nociceptor-dependent inflammation plays a significant pathological role, are protected from the development of allodynia and joint inflammation. Thus, nociceptor HMGB1 is required to mediate pain and inflammation during sciatic nerve injury and collagen antibody-induced arthritis.
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http://dx.doi.org/10.1073/pnas.2102034118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8379951PMC
August 2021

Women with Fibromyalgia Prefer Resistance Exercise with Heavy Loads-A Randomized Crossover Pilot Study.

Int J Environ Res Public Health 2021 06 10;18(12). Epub 2021 Jun 10.

School of Health and Welfare, Medical Science, Dalarna University, 791 88 Falun, Sweden.

Fibromyalgia (FM) is a chronic pain condition associated with impaired muscle strength and exercise-induced pain. Physical exercise has been highlighted, by international clinical guidelines and stakeholders, as an essential component of rehabilitation in FM. Exposure to pain during exercise is generally correlated with elevated lactate levels and, additionally, is one known reason for persons with FM to avoid physical exercise and activity. A crossover design was used to test and evaluate an approach consisting of resistance exercise with heavy loads and a low number of repetitions among ten women with FM. The participants were consecutively recruited to test and perform exercise with two different resistance levels (A = light/moderate load, and B = heavy load) in a randomized crossover trial using an AB/BA setting. Results showed that the heavy load exercise session was experienced as more positive than the light/moderate load exercise session and that lower lactate levels followed exercise with heavier weight loads. This is promising and indicates that the approach of heavy weight loads and accustomed repetitions is accepted in FM and has the potential to attenuate hesitation to exercise due to exercise-induced pain. However, these effects need to be further investigated in more extensive studies.
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http://dx.doi.org/10.3390/ijerph18126276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8296097PMC
June 2021

Redox modifications of cysteine residues regulate the cytokine activity of HMGB1.

Mol Med 2021 06 7;27(1):58. Epub 2021 Jun 7.

Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, Manhasset, NY, USA.

Background: High mobility group box 1 (HMGB1) is a nuclear protein with extracellular inflammatory cytokine activity. It is passively released during cell death and secreted by activated cells of many lineages. HMGB1 contains three conserved redox-sensitive cysteine residues: cysteines in position 23 and 45 (C23 and C45) can form an intramolecular disulfide bond, whereas C106 is unpaired and is essential for the interaction with Toll-Like Receptor (TLR) 4. However, a comprehensive characterization of the dynamic redox states of each cysteine residue and of their impacts on innate immune responses is lacking.

Methods: Primary human macrophages or murine macrophage-like RAW 264.7 cells were activated in cell cultures by redox-modified or point-mutated (C45A) recombinant HMGB1 preparations or by lipopolysaccharide (E. coli.0111: B4). Cellular phosphorylated NF-κB p65 subunit and subsequent TNF-α release were quantified by commercial enzyme-linked immunosorbent assays.

Results: Cell cultures with primary human macrophages and RAW 264.7 cells demonstrated that fully reduced HMGB1 with all three cysteines expressing thiol side chains failed to generate phosphorylated NF-КB p65 subunit or TNF-α. Mild oxidation forming a C23-C45 disulfide bond, while leaving C106 with a thiol group, was required for HMGB1 to induce phosphorylated NF-КB p65 subunit and TNF-α production. The importance of a C23-C45 disulfide bond was confirmed by mutation of C45 to C45A HMGB1, which abolished the ability for cytokine induction. Further oxidation of the disulfide isoform also inactivated HMGB1.

Conclusions: These results reveal critical post-translational redox mechanisms that control the proinflammatory activity of HMGB1 and its inactivation during inflammation.
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http://dx.doi.org/10.1186/s10020-021-00307-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8185929PMC
June 2021

An oral antisense oligonucleotide for PCSK9 inhibition.

Sci Transl Med 2021 05;13(593)

Advanced Drug Delivery, Pharmaceutical Sciences, R&D, AstraZeneca, SE-431 50 Gothenburg, Sweden.

Inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9) reduce low-density lipoprotein (LDL) cholesterol and are used for treatment of dyslipidemia. Current PCSK9 inhibitors are administered via subcutaneous injection. We present a highly potent, chemically modified PCSK9 antisense oligonucleotide (ASO) with potential for oral delivery. Past attempts at oral delivery using earlier-generation ASO chemistries and transient permeation enhancers provided encouraging data, suggesting that improving potency of the ASO could make oral delivery a reality. The constrained ethyl chemistry and liver targeting enabled by -acetylgalactosamine conjugation make this ASO highly potent. A single subcutaneous dose of 90 mg reduced PCSK9 by >90% in humans with elevated LDL cholesterol and a monthly subcutaneous dose of around 25 mg is predicted to reduce PCSK9 by 80% at steady state. To investigate the feasibility of oral administration, the ASO was coformulated in a tablet with sodium caprate as permeation enhancer. Repeated oral daily dosing in dogs resulted in a bioavailability of 7% in the liver (target organ), about fivefold greater than the plasma bioavailability. Target engagement after oral administration was confirmed by intrajejunal administration of a rat-specific surrogate ASO in solution with the enhancer to rats and by plasma PCSK9 and LDL cholesterol lowering in cynomolgus monkey after tablet administration. On the basis of an assumption of 5% liver bioavailability after oral administration in humans, a daily dose of 15 mg is predicted to reduce circulating PCSK9 by 80% at steady state, supporting the development of the compound for oral administration to treat dyslipidemia.
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http://dx.doi.org/10.1126/scitranslmed.abe9117DOI Listing
May 2021

Therapeutic administration of etoposide coincides with reduced systemic HMGB1 levels in macrophage activation syndrome.

Mol Med 2021 05 11;27(1):48. Epub 2021 May 11.

Department of Women's and Children's Health, Karolinska Institute at Karolinska University Hospital, 17176, Stockholm, Sweden.

Background: Macrophage activation syndrome (MAS) is a potentially fatal complication of systemic inflammation. HMGB1 is a nuclear protein released extracellularly during proinflammatory lytic cell death or secreted by activated macrophages, NK cells, and additional cell types during infection or sterile injury. Extracellular HMGB1 orchestrates central events in inflammation as a prototype alarmin. TLR4 and the receptor for advanced glycation end products operate as key HMGB1 receptors to mediate inflammation.

Methods: Standard ELISA and cytometric bead array-based methods were used to examine the kinetic pattern for systemic release of HMGB1, ferritin, IL-18, IFN-γ, and MCP-1 before and during treatment of four children with critical MAS. Three of the patients with severe underlying systemic rheumatic diseases were treated with biologics including tocilizumab or anakinra when MAS developed. All patients required intensive care therapy due to life-threatening illness. Add-on etoposide therapy was administered due to insufficient clinical response with standard treatment. Etoposide promotes apoptotic rather than proinflammatory lytic cell death, conceivably ameliorating subsequent systemic inflammation.

Results: This therapeutic intervention brought disease control coinciding with a decline of the increased systemic HMGB1, IFN-γ, IL-18, and ferritin levels whereas MCP-1 levels evolved independently.

Conclusion: Systemic HMGB1 levels in MAS have not been reported before. Our results suggest that the molecule is not merely a biomarker of inflammation, but most likely also contributes to the pathogenesis of MAS. These observations encourage further studies of HMGB1 antagonists. They also advocate therapeutic etoposide administration in severe MAS and provide a possible biological explanation for its mode of action.
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http://dx.doi.org/10.1186/s10020-021-00308-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8111379PMC
May 2021

Hyperinflammation: On the pathogenesis and treatment of macrophage activation syndrome.

Authors:
Ulf Andersson

Acta Paediatr 2021 Oct 11;110(10):2717-2722. Epub 2021 May 11.

Department of Women's and Children's Health, Karolinska Institutet at Karolinska University Hospital, Stockholm, Sweden.

Macrophage activation syndrome (MAS) is a subtype of hemophagocytic lymphohistiocytosis (HLH) diseases. The underlying mechanism of these life-threatening disorders is impaired granule-mediated cytotoxicity exerted by natural killer (NK) cells and T lymphocytes. This function is meant for elimination of virus-infected cells, malignant cells and to prevent exaggerated immune responses. The normal outcome after an attack by NK or cytotoxic T cells is apoptosis of the target cell. This prevents cytotoxic inflammatory responses in adjacent tissues which occur after lytic cell death. Extensive cell lysis can even produce a cytokine storm, as evidenced in MAS. Programmed proinflammatory lytic cell death, pyroptosis, caused by activated inflammasomes is central in the pathogenesis of MAS. Pyroptosis mediates IL-18 cytokine release, which robustly stimulates NK and T cells to produce IFN-γ, the key macrophage-activating signal which initiates a burst of inflammatory cytokines and chemokines. Lytic cell death also mediates a discharge of the prototype alarmin high mobility group box protein 1 (HMGB1), a proinflammatory molecule present in all cells and that mediates the pathogenesis of MAS as outlined here. Therapeutic options to control causal factors operating in the pathogenesis of MAS are also discussed.
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http://dx.doi.org/10.1111/apa.15900DOI Listing
October 2021

Efficacy of Moderately Dosed Etoposide in Macrophage Activation Syndrome-Hemophagocytic Lymphohistiocytosis.

J Rheumatol 2021 10 15;48(10):1596-1602. Epub 2021 Feb 15.

T. von Bahr Greenwood, MD, J.I. Henter, Professor, MD, PhD, Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, and Theme of Children's Health, Karolinska University Hospital, Stockholm.

Objective: Macrophage activation syndrome (MAS) constitutes 1 subtype of the hyperinflammatory syndrome hemophagocytic lymphohistiocytosis (HLH), and the term MAS-HLH was recently proposed for HLH with underlying autoimmune/autoinflammatory conditions. The mortality of MAS-HLH has been estimated at 5-10%. Here we report our experiences with moderately dosed etoposide in severe MAS-HLH; the objective was to effectively reduce severe hyperinflammatory activity with limited side effects.

Methods: In addition to conventional antiinflammatory treatment, moderately dosed etoposide was administered to 7 children affected by rapidly progressing MAS-HLH with central nervous system (n = 5) and/or pulmonary (n = 5) involvement. Three had underlying systemic juvenile idiopathic arthritis (sJIA), 2 had atypical sJIA (no arthritis at diagnosis), and 2 had systemic lupus erythematosus. We performed lymphocyte cytotoxicity analyses in all 7 and genetic analyses in 6.

Results: All children promptly responded to moderately dosed etoposide (50-100 mg/m once weekly), added to conventional MAS-HLH treatment that was considered insufficient. The mean accumulated etoposide dose was 671 mg/m (range 300-1050 mg/m) as compared to 1500 mg/m recommended in the first 8 weeks of the HLH-94/HLH-2004 protocols. One child developed neutropenic fever and another neutropenic sepsis (neutrophils 0.3 × 10/L at therapy onset). Five of 7 children had low percentages (< 5%) of circulating natural killer (NK) cells prior to or in association with diagnosis; NK cell activity was pathologically low in 2 of 5 children studied. Disease-causing variants in HLH-associated genes were not found. All children were alive at latest follow-up (2-9 yrs after onset); neurological symptoms had normalized in 4 of 5 affected children.

Conclusion: Moderately dosed etoposide may be beneficial in severe and/or refractory MAS-HLH.
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http://dx.doi.org/10.3899/jrheum.200941DOI Listing
October 2021

Heparin prevents caspase-11-dependent septic lethality independent of anticoagulant properties.

Immunity 2021 03 8;54(3):454-467.e6. Epub 2021 Feb 8.

Department of Critical Care Medicine and Hematology, The 3rd Xiangya Hospital, Central South University, Changsha, 410000 P.R. China; Department of Pathophysiology, School of Basic Medical Science, Central South University, Changsha, Hunan Province, 410000 P.R. China; Key Laboratory of sepsis translational medicine of Hunan, Central South University, Changsha, Hunan Province, 410000 P.R. China. Electronic address:

Heparin, a mammalian polysaccharide, is a widely used anticoagulant medicine to treat thrombotic disorders. It is also known to improve outcomes in sepsis, a leading cause of mortality resulted from infection-induced immune dysfunction. Whereas it is relatively clear how heparin exerts its anticoagulant effect, the immunomodulatory mechanisms enabled by heparin remain enigmatic. Here, we show that heparin prevented caspase-11-dependent immune responses and lethality in sepsis independent of its anticoagulant properties. Heparin or a chemically modified form of heparin without anticoagulant function inhibited the alarmin HMGB1-lipopolysaccharide (LPS) interaction and prevented the macrophage glycocalyx degradation by heparanase. These events blocked the cytosolic delivery of LPS in macrophages and the activation of caspase-11, a cytosolic LPS receptor that mediates lethality in sepsis. Survival was higher in septic patients treated with heparin than those without heparin treatment. The identification of this previously unrecognized heparin function establishes a link between innate immune responses and coagulation.
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http://dx.doi.org/10.1016/j.immuni.2021.01.007DOI Listing
March 2021

Retraction Note to: High systemic levels of the cytokine-inducing HMGB1 isoform secreted in severe macrophage activation syndrome.

Mol Med 2020 Dec 30;26(1):131. Epub 2020 Dec 30.

Unit of Pediatric Rheumatology, Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital, Solna, 171 76, Stockholm, Sweden.

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http://dx.doi.org/10.1186/s10020-020-00263-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772904PMC
December 2020

Identification of a brainstem locus that inhibits tumor necrosis factor.

Proc Natl Acad Sci U S A 2020 11 9;117(47):29803-29810. Epub 2020 Nov 9.

Institute of Bioelectronic Medicine, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY 11030;

In the brain, compact clusters of neuron cell bodies, termed nuclei, are essential for maintaining parameters of host physiology within a narrow range optimal for health. Neurons residing in the brainstem dorsal motor nucleus (DMN) project in the vagus nerve to communicate with the lungs, liver, gastrointestinal tract, and other organs. Vagus nerve-mediated reflexes also control immune system responses to infection and injury by inhibiting the production of tumor necrosis factor (TNF) and other cytokines in the spleen, although the function of DMN neurons in regulating TNF release is not known. Here, optogenetics and functional mapping reveal cholinergic neurons in the DMN, which project to the celiac-superior mesenteric ganglia, significantly increase splenic nerve activity and inhibit TNF production. Efferent vagus nerve fibers terminating in the celiac-superior mesenteric ganglia form varicose-like structures surrounding individual nerve cell bodies innervating the spleen. Selective optogenetic activation of DMN cholinergic neurons or electrical activation of the cervical vagus nerve evokes action potentials in the splenic nerve. Pharmacological blockade and surgical transection of the vagus nerve inhibit vagus nerve-evoked splenic nerve responses. These results indicate that cholinergic neurons residing in the brainstem DMN control TNF production, revealing a role for brainstem coordination of immunity.
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http://dx.doi.org/10.1073/pnas.2008213117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7703602PMC
November 2020

The regulatory role of PGC1α-related coactivator in response to drug-induced liver injury.

FASEB Bioadv 2020 Aug 11;2(8):453-463. Epub 2020 Jul 11.

Clinical Pharmacology and Safety Sciences AstraZeneca R&D Mölndal Sweden.

PGC1α-Related Coactivator (PRC) is a transcriptional coactivator promoting cytokine expression in vitro in response to mitochondrial injury and oxidative stress, however, its physiological role has remained elusive. Herein we investigate aspects of the immune response function of PRC, first in an in vivo thioacetamide (TAA)-induced mouse model of drug-induced liver injury (DILI), and subsequently in vitro in human monocytes, HepG2, and dendritic (DC) cells. TAA treatment resulted in the dose-dependent induction of PRC mRNA and protein, both of which were shown to correlate with liver injury markers. Conversely, an adenovirus-mediated knockdown of PRC attenuated this response, thereby reducing hepatic cytokine mRNA expression and monocyte infiltration. Subsequent in vitro studies with conditioned media from HepG2 cells overexpressing PRC, activated human monocytes and monocyte-derived DC, demonstrated up to 20% elevated expression of CD86, CD40, and HLA-DR. Similarly, siRNA-mediated knockdown of PRC abolished this response in oligomycin stressed HepG2 cells. A putative mechanism was suggested by the co-immunoprecipitation of Signal Transducer and Activator of Transcription 1 (STAT1) with PRC, and induction of a STAT-dependent reporter. Furthermore, PRC co-activated an NF-κB-dependent reporter, indicating interaction with known major inflammatory factors. In summary, our study indicates PRC as a novel factor modulating inflammation in DILI.
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http://dx.doi.org/10.1096/fba.2020-00003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429352PMC
August 2020

Identification and Optimization of Pyrrolidine Derivatives as Highly Potent Ghrelin Receptor Full Agonists.

J Med Chem 2020 09 27;63(17):9705-9730. Epub 2020 Aug 27.

Precision Medicine, Oncology R&D, AstraZeneca, Mölndal SE-43183, Sweden.

Muscle atrophy and cachexia are common comorbidities among patients suffering from cancer, chronic obstructive pulmonary disease, and several other chronic diseases. The peptide hormone ghrelin exerts pleiotropic effects including the stimulation of growth hormone secretion and subsequent increase of insulin-like growth factor-1 levels, an important mediator of muscle growth and repair. Ghrelin also acts on inflammation, appetite, and adipogenesis and therefore has been considered a promising therapeutic target for catabolic conditions. We previously reported on the synthesis and properties of an indane based series of ghrelin receptor full agonists which led to a sustained increase of insulin-like growth factor-1 in a dog pharmacodynamic study. Herein we report on the identification of a series of pyrrolidine or piperidine based full agonists and attempted optimization to give compounds with profiles suitable for progression as clinical candidates.
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http://dx.doi.org/10.1021/acs.jmedchem.0c00828DOI Listing
September 2020

The cholinergic anti-inflammatory pathway alleviates acute lung injury.

Authors:
Ulf Andersson

Mol Med 2020 06 29;26(1):64. Epub 2020 Jun 29.

Department of Women's and Children's Health, Karolinska Institutet at Karolinska University Hospital, Tomtebodavägen 18A, 17176, Stockholm, Sweden.

The ubiquiotous nuclear protein HMGB1 is extracellularly released by dying cells or activated innate immunity cells to promote inflammation. Extracellular HMGB1 plays a prominent role in the pathogenesis of acute lung injury of infectious as well as sterile origin including hyperoxia. Excessive amounts of systemic HMGB1 and HMGB1-partner molecule complexes can be retained in the pulmonary circulation indicated by a substantial reduction of HMGB1 plasma levels in arterial versus venous blood. The cholinergic antiinflammatory mechanism ameliorates pulmonary inflammation by inhibiting HMGB1 release and HMGB1 receptor expression. This comprehension was recently reinforced by results reported in Molecular Medicine by Sitapara and coworkers demonstrating that administration of an α7 nicotinic acetylcholine receptor agonist attenuated hyperoxia-induced acute inflammatory lung injury by alleviating the accumulation of HMGB1 in the airways and the circulation. Activating the cholinergic antiinflammatory path might be considered to alleviate severe COVID-19 with or without concurrent oxygen-induced lung injury.
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http://dx.doi.org/10.1186/s10020-020-00184-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7322708PMC
June 2020

Extracellular HMGB1: a therapeutic target in severe pulmonary inflammation including COVID-19?

Mol Med 2020 05 7;26(1):42. Epub 2020 May 7.

Center for Biomedical Science and Bioelectronic Medicine, Feinstein Institutes for Medical Research, Northwell Health, 350 Community Drive, Manhasset, NY, 11030, USA.

Background: The 2019 novel coronavirus disease (COVID-19) causes for unresolved reasons acute respiratory distress syndrome in vulnerable individuals. There is a need to identify key pathogenic molecules in COVID-19-associated inflammation attainable to target with existing therapeutic compounds. The endogenous damage-associated molecular pattern (DAMP) molecule HMGB1 initiates inflammation via two separate pathways. Disulfide-HMGB1 triggers TLR4 receptors generating pro-inflammatory cytokine release. Extracellular HMGB1, released from dying cells or secreted by activated innate immunity cells, forms complexes with extracellular DNA, RNA and other DAMP or pathogen-associated molecular (DAMP) molecules released after lytic cell death. These complexes are endocytosed via RAGE, constitutively expressed at high levels in the lungs only, and transported to the endolysosomal system, which is disrupted by HMGB1 at high concentrations. Danger molecules thus get access to cytosolic proinflammatory receptors instigating inflammasome activation. It is conceivable that extracellular SARS-CoV-2 RNA may reach the cellular cytosol via HMGB1-assisted transfer combined with lysosome leakage. Extracellular HMGB1 generally exists in vivo bound to other molecules, including PAMPs and DAMPs. It is plausible that these complexes are specifically removed in the lungs revealed by a 40% reduction of HMGB1 plasma levels in arterial versus venous blood. Abundant pulmonary RAGE expression enables endocytosis of danger molecules to be destroyed in the lysosomes at physiological HMGB1 levels, but causing detrimental inflammasome activation at high levels. Stress induces apoptosis in pulmonary endothelial cells from females but necrosis in cells from males.

Conclusion: Based on these observations we propose extracellular HMGB1 to be considered as a therapeutic target for COVID-19.
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http://dx.doi.org/10.1186/s10020-020-00172-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7203545PMC
May 2020

Targeting Inflammation Driven by HMGB1.

Front Immunol 2020 20;11:484. Epub 2020 Mar 20.

Department of Women's and Children's Health, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.

High mobility group box 1 (HMGB1) is a highly conserved, nuclear protein present in all cell types. It is a multi-facet protein exerting functions both inside and outside of cells. Extracellular HMGB1 has been extensively studied for its prototypical alarmin functions activating innate immunity, after being actively released from cells or passively released upon cell death. TLR4 and RAGE operate as the main HMGB1 receptors. Disulfide HMGB1 activates the TLR4 complex by binding to MD-2. The binding site is separate from that of LPS and it is now feasible to specifically interrupt HMGB1/TLR4 activation without compromising protective LPS/TLR4-dependent functions. Another important therapeutic strategy is established on the administration of HMGB1 antagonists precluding RAGE-mediated endocytosis of HMGB1 and HMGB1-bound molecules capable of activating intracellular cognate receptors. Here we summarize the role of HMGB1 in inflammation, with a focus on recent findings on its mission as a damage-associated molecular pattern molecule and as a therapeutic target in inflammatory diseases. Recently generated HMGB1-specific inhibitors for treatment of inflammatory conditions are discussed.
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http://dx.doi.org/10.3389/fimmu.2020.00484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7099994PMC
March 2021

Prolonged elevation of plasma HMGB1 is associated with cognitive impairment in intensive care unit survivors.

Intensive Care Med 2020 04 26;46(4):811-812. Epub 2020 Feb 26.

Laboratory of Immunobiology, Center for Bioelectronic Medicine, Department of Medicine, Solna, Karolinska Institute, Bioclinicum, Karolinska University Hospital, 171 76, Stockholm, Sweden.

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http://dx.doi.org/10.1007/s00134-020-05941-7DOI Listing
April 2020

Expression of concern to: High systemic levels of the cytokine-inducing HMGB1 isoform secreted in severe macrophage activation syndrome.

Mol Med 2020 02 3;26(1):17. Epub 2020 Feb 3.

Unit of Pediatric Rheumatology, Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital, Solna, Karolinska Institutet, Stockholm, Sweden.

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http://dx.doi.org/10.1186/s10020-020-0142-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6998297PMC
February 2020

Clinical reasoning in the emergency medical services: an integrative review.

Scand J Trauma Resusc Emerg Med 2019 Aug 19;27(1):76. Epub 2019 Aug 19.

Faculty of Caring Science, Work Life, and Social Welfare, University of Borås, Borås, Sweden.

Clinical reasoning is the process of gathering and understanding information conducted by clinicians in the emergency medical services (EMS) so as to make informed decisions. Research on clinical reasoning spans several disciplines, but a comprehensive view of the process is lacking. To our knowledge, no review of clinical reasoning in the EMS has been conducted.

Aim: The aim was to investigate the nature, deployment, and factors influencing EMS clinicians' clinical reasoning by means of a review.

Method: Data was collected through searches in electronic databases, networking among research teams, colleagues and friends, "grey literature," and through ancestry searches. A total of 38 articles were deemed eligible for inclusion and were analyzed using descriptive thematic analysis. The analysis resulted in an overarching finding - namely, the importance for EMS clinicians to adjust for perceived control in unpredictable situations. Within this finding, 3 themes emerged in terms of EMS clinicians' clinical reasoning: (1) maintaining a holistic view of the patient; (2) keeping an open mind; and (3) improving through criticism. Seven subthemes subsequently emerged from these three themes.

Results: This review showed that EMS clinicians' clinical reasoning begins with the information that they are given about a patient. Based on this information, clinicians calculate the best route to the patient and which equipment to use, and they also assess potential risks. They need to be constantly aware of what is happening on the scene and with the patient and strive to control the situation. This striving also enables EMS clinicians to work safely and effectively in relation to the patient, their relatives, other clinicians, associated organizations, and the wider community. A lack of contextually appropriate guidelines results in the need for creativity and forces EMS clinicians to use "workarounds" to solve issues beyond the scope of the guidelines available. In addition, they often lack organizational support and fear repercussions such as litigation, unemployment, or blame by their EMS or healthcare organization or by patients and relatives.

Conclusion: Clinical reasoning is influenced by several factors. Further research is needed to determine which influencing factors can be addressed through interventions to minimize their impact on patient outcomes.
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http://dx.doi.org/10.1186/s13049-019-0646-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6700770PMC
August 2019

Discovery of the Oral Leukotriene C4 Synthase Inhibitor (1,2)-2-({5-[(5-Chloro-2,4-difluorophenyl)(2-fluoro-2-methylpropyl)amino]-3-methoxypyrazin-2-yl}carbonyl)cyclopropanecarboxylic Acid (AZD9898) as a New Treatment for Asthma.

J Med Chem 2019 09 30;62(17):7769-7787. Epub 2019 Aug 30.

Orexo AB , Virdings allé 32A , SE-75450 Uppsala , Sweden.

While bronchodilators and inhaled corticosteroids are the mainstay of asthma treatment, up to 50% of asthmatics remain uncontrolled. Many studies show that the cysteinyl leukotriene cascade remains highly activated in some asthmatics, even those on high-dose inhaled or oral corticosteroids. Hence, inhibition of the leukotriene C4 synthase (LTC4S) enzyme could provide a new and differentiated core treatment for patients with a highly activated cysteinyl leukotriene cascade. Starting from a screening hit (), a program to discover oral inhibitors of LTC4S led to (1,2)-2-({5-[(5-chloro-2,4-difluorophenyl)(2-fluoro-2-methylpropyl)amino]-3-methoxypyrazin-2-yl}carbonyl)cyclopropanecarboxylic acid (AZD9898) (), a picomolar LTC4S inhibitor (IC = 0.28 nM) with high lipophilic ligand efficiency (LLE = 8.5), which displays nanomolar potency in cells (peripheral blood mononuclear cell, IC = 6.2 nM) and good in vivo pharmacodynamics in a calcium ionophore-stimulated rat model after oral dosing (in vivo, IC = 34 nM). Compound mitigates the GABA binding, hepatic toxicity signal, and in vivo toxicology findings of an early lead compound with a human dose predicted to be 30 mg once daily.
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http://dx.doi.org/10.1021/acs.jmedchem.9b00555DOI Listing
September 2019

An Angle on MK2 Inhibition-Optimization and Evaluation of Prevention of Activation Inhibitors.

ChemMedChem 2019 10 13;14(19):1701-1709. Epub 2019 Aug 13.

Clinical Pharmacology and Safety Sciences, R&D Biopharmaceuticals, AstraZeneca, Gothenburg, Pepparedsleden 1, 431 83, Mölndal, Sweden.

The mitogen-activated protein kinase p38α pathway has been an attractive target for the treatment of inflammatory conditions such as rheumatoid arthritis. While a number of p38α inhibitors have been taken to the clinic, they have been limited by their efficacy and toxicological profile. A lead identification program was initiated to selectively target prevention of activation (PoA) of mitogen-activated protein kinase-activated protein kinase 2 (MK2) rather than mitogen- and stress-activated protein kinase 1 (MSK1), both immediate downstream substrates of p38α, to improve the efficacy/safety profile over direct p38α inhibition. Starting with a series of pyrazole amide PoA MK2 inhibitor leads, and guided by structural chemistry and rational design, a highly selective imidazole 9 (2-(3'-(2-amino-2-oxoethyl)-[1,1'-biphenyl]-3-yl)-N-(5-(N,N-dimethylsulfamoyl)-2-methylphenyl)-1-propyl-1H-imidazole-5-carboxamide) and the orally bioavailable imidazole 18 (3-methyl-N-(2-methyl-5-sulfamoylphenyl)-2-(o-tolyl)imidazole-4-carboxamide) were discovered. The PoA concept was further evaluated by protein immunoblotting, which showed that the optimized PoA MK2 compounds, despite their biochemical selectivity against MSK1 phosphorylation, behaved similarly to p38 inhibitors in cellular signaling. This study highlights the importance of selective tool compounds in untangling complex signaling pathways, and although 9 and 18 were not differentiated from p38α inhibitors in a cellular context, they are still useful tools for further research directed to understand the role of MK2 in the p38α signaling pathway.
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http://dx.doi.org/10.1002/cmdc.201900303DOI Listing
October 2019

Biphasic Release of the Alarmin High Mobility Group Box 1 Protein Early After Trauma Predicts Poor Clinical Outcome.

Crit Care Med 2019 08;47(8):e614-e622

Department of Anaesthesiology, Oslo University Hospital, Oslo, Norway.

Objectives: The causal role of the prototype alarmin high mobility group box 1 protein in systemic inflammation and remote organ injury after trauma and shock is established in animal models but not in humans. Our aim was therefore to determine high mobility group box 1 protein concentration kinetics with high time resolution during the first hours after trauma in individual patients and investigate the association with outcome.

Design: Prospective single-center observational study.

Setting: University hospital Level I trauma center.

Patients: Convenience recruitment of 136 trauma patients.

Interventions: None.

Measurements And Main Results: Total plasma high mobility group box 1 protein levels were analyzed with enzyme-linked immunosorbent assay in repeated samples. Relationships between predefined predictor variables and outcome were examined in multivariable linear regression models. Ventilator-free days was used as primary outcome measure. Two distinct high mobility group box 1 protein release phases were identified. An initial exponential decay phase with half-life 26 minutes was not correlated with outcome. In contrast, a second high mobility group box 1 protein wave peaking 3-6 hours after trauma in the most severely injured and physiologically deranged patients was consistently the most important predictor of outcome in our multivariable models, rendering all other predictor variables insignificant except for smaller contributions from age and sex, and of admission base excess for maximal creatinine concentration.

Conclusions: High mobility group box 1 protein was released in two consecutive phases. Only the second high mobility group box 1 protein wave was a significant predictor of outcome. Patients with a high high mobility group box 1 protein concentration between 3 and 6 hours after trauma might hypothetically benefit from high mobility group box 1 protein-specific antagonist therapy.
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http://dx.doi.org/10.1097/CCM.0000000000003800DOI Listing
August 2019

Global Fe-O isotope correlation reveals magmatic origin of Kiruna-type apatite-iron-oxide ores.

Nat Commun 2019 04 12;10(1):1712. Epub 2019 Apr 12.

Department of Mineral Resources, Geological Survey of Sweden, Villavägen 18, Box 670, 75128, Uppsala, Sweden.

Kiruna-type apatite-iron-oxide ores are key iron sources for modern industry, yet their origin remains controversial. Diverse ore-forming processes have been discussed, comprising low-temperature hydrothermal processes versus a high-temperature origin from magma or magmatic fluids. We present an extensive set of new and combined iron and oxygen isotope data from magnetite of Kiruna-type ores from Sweden, Chile and Iran, and compare them with new global reference data from layered intrusions, active volcanic provinces, and established low-temperature and hydrothermal iron ores. We show that approximately 80% of the magnetite from the investigated Kiruna-type ores exhibit δFe and δO ratios that overlap with the volcanic and plutonic reference materials (> 800 °C), whereas ~20%, mainly vein-hosted and disseminated magnetite, match the low-temperature reference samples (≤400 °C). Thus, Kiruna-type ores are dominantly magmatic in origin, but may contain late-stage hydrothermal magnetite populations that can locally overprint primary high-temperature magmatic signatures.
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http://dx.doi.org/10.1038/s41467-019-09244-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6461606PMC
April 2019

Inhibition of HMGB1/RAGE-mediated endocytosis by HMGB1 antagonist box A, anti-HMGB1 antibodies, and cholinergic agonists suppresses inflammation.

Mol Med 2019 04 11;25(1):13. Epub 2019 Apr 11.

Center for Biomedical Science The Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY, 11030, USA.

Background: Extracellular high mobility group box 1 protein  (HMGB1) serves a central role in inflammation as a transporter protein, which binds other immune-activating molecules that are endocytosed via the receptor for advanced glycation end-products (RAGE). These pro-inflammatory complexes are targeted to the endolysosomal compartment, where HMGB1 permeabilizes the lysosomes. This enables HMGB1-partner molecules to avoid degradation, to leak into the cytosol, and to reach cognate immune-activating sensors. Lipopolysaccharide (LPS) requires this pathway to generate pyroptosis by accessing its key cytosolic receptors, murine caspase 11, or the human caspases 4 and 5. This lytic, pro-inflammatory cell death plays a fundamental pathogenic role in gram-negative sepsis. The aim of the study was to identify molecules inhibiting HMGB1 or HMGB1/LPS cellular internalization.

Methods: Endocytosis was studied in cultured macrophages using Alexa Fluor-labeled HMGB1 or complexes of HMGB1 and Alexa Fluor-labeled LPS in the presence of an anti-HMGB1 monoclonal antibody (mAb), recombinant HMGB1 box A protein, acetylcholine, the nicotinic acetylcholine receptor subtype alpha 7 (α7 nAChR) agonist GTS-21, or a dynamin-specific inhibitor of endocytosis. Images were obtained by fluorescence microscopy and quantified by the ImageJ processing program (NIH). Data were analyzed using student's t test or one-way ANOVA followed by the least significant difference or Tukey's tests.

Results: Anti-HMGB1 mAb, recombinant HMGB1 antagonist box A protein, acetylcholine, GTS-21, and the dynamin-specific inhibitor of endocytosis inhibited internalization of HMGB1 or HMGB1-LPS complexes in cultured macrophages. These agents prevented macrophage activation in response to HMGB1 and/or HMGB1-LPS complexes.

Conclusion: These results demonstrate that therapies based on HMGB1 antagonists and the cholinergic anti-inflammatory pathway share a previously unrecognized molecular mechanism of substantial clinical relevance.
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http://dx.doi.org/10.1186/s10020-019-0081-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6460792PMC
April 2019

Therapeutic blockade of HMGB1 reduces early motor deficits, but not survival in the SOD1 mouse model of amyotrophic lateral sclerosis.

J Neuroinflammation 2019 Feb 19;16(1):45. Epub 2019 Feb 19.

Faculty of Medicine, School of Biomedical Sciences, The University of Queensland, St Lucia, Brisbane, QLD, 4072, Australia.

Background: Amyotrophic lateral sclerosis (ALS) is a fatal and rapidly progressing neurodegenerative disease without effective treatment. The receptor for advanced glycation end products (RAGE) and the toll-like receptor (TLR) system are major components of the innate immune system, which have been implicated in ALS pathology. Extracellularly released high-mobility group box 1 (HMGB1) is a pleiotropic danger-associated molecular pattern (DAMP), and is an endogenous ligand for both RAGE and TLR4.

Methods: The present study examined the effect of HMGB1 inhibition on disease progression in the preclinical SOD1 transgenic mouse model of ALS using a potent anti-HMGB1 antibody (2G7), which targets the extracellular DAMP form of HMGB1.

Results: We found that chronic intraperitoneal dosing of the anti-HMGB1 antibody to SOD1 mice transiently improved hind-limb grip strength early in the disease, but did not extend survival. Anti-HMGB1 treatment also reduced tumour necrosis factor α and complement C5a receptor 1 gene expression in the spinal cord, but did not affect overall glial activation.

Conclusions: In summary, our results indicate that therapeutic targeting of an extracellular DAMP, HMGB1, improves early motor dysfunction, but overall has limited efficacy in the SOD1 mouse model of ALS.
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http://dx.doi.org/10.1186/s12974-019-1435-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6380064PMC
February 2019

Adenylyl Cyclase 6 Mediates Inhibition of TNF in the Inflammatory Reflex.

Front Immunol 2018 27;9:2648. Epub 2018 Nov 27.

Department of Medicine, Center for Bioelectronic Medicine, Center for Molecular Medicine, Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.

Macrophage cytokine production is regulated by neural signals, for example in the inflammatory reflex. Signals in the vagus and splenic nerves are relayed by choline acetyltransferase T cells that release acetylcholine, the cognate ligand for alpha7 nicotinic acetylcholine subunit-containing receptors (α7nAChR), and suppress TNF release in macrophages. Here, we observed that electrical vagus nerve stimulation with a duration of 0.1-60 s significantly reduced systemic TNF release in experimental endotoxemia. This suppression of TNF was sustained for more than 24 h, but abolished in mice deficient in the α7nAChR subunit. Exposure of primary human macrophages and murine RAW 264.7 macrophage-like cells to selective ligands for α7nAChR for 1 h attenuated TNF production for up to 24 h in response to endotoxin. Pharmacological inhibition of adenylyl cyclase (AC) and knockdown of adenylyl cyclase 6 (AC6) or c-FOS abolished cholinergic suppression of endotoxin-induced TNF release. These findings indicate that action potentials in the inflammatory reflex trigger a change in macrophage behavior that requires AC and phosphorylation of the cAMP response element binding protein (CREB). These observations further our mechanistic understanding of neural regulation of inflammation and may have implications for development of bioelectronic medicine treatment of inflammatory diseases.
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http://dx.doi.org/10.3389/fimmu.2018.02648DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6277584PMC
September 2019

Identification of ethyl pyruvate as a NLRP3 inflammasome inhibitor that preserves mitochondrial integrity.

Mol Med 2018 03 15;24(1). Epub 2018 Mar 15.

Laboratory of Biomedical Science, Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY, 11030, USA.

Background: The NLRP3 inflammasome, a cytosolic complex that mediates the maturation of IL-1β and IL-18 as well as the release of high mobility group box 1 (HMGB1), contributes to the lethality of endotoxic shock. Ethyl pyruvate (EP) was previously shown to inhibit HMGB1 release and promote survival during endotoxemia and experimental sepsis. However, the underlying protective mechanism remains elusive.

Result: EP dose-dependently inhibited the ATP-, nigericin-, alum-, and silica-induced caspase-1 activation and HMGB1 release in mouse macrophages. EP failed to inhibit DNA transfection- or Salmonella Typhimurium-induced caspase-1 activation and HMGB1 release. Mechanistically, EP significantly attenuated mitochondrial damage and cytoplasmic translocation of mitochondrial DNA, a known NLRP3 ligand, without influencing the potassium efflux, the lysosomal rupture or the production of mitochondrial reactive oxygen species (mtROS).

Conclusion: Ethyl pyruvate acts as a novel NLRP3 inflammasome inhibitor that preserves the integrity of mitochondria during inflammation.
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http://dx.doi.org/10.1186/s10020-018-0006-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6016887PMC
March 2018
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