Abstract:We evaluated the efficacy of a neutralizing anti-high mobility group box 1 (HMGB1) monoclonal antibody in MRL/lpr lupus-prone mice. The anti-HMGB1 monoclonal antibody (5 mg/kg weight) or class-matched control immunoglobulin G2a (IgG2a) was administered intravenously twice a week for 4–15 weeks. Urine albumin was monitored, and histological evaluation of the kidneys was conducted at 16 weeks. Lymphadenopathies were evaluated by 1-(2′-deoxy-2′-[18F]fluoro-β-D-arabinofuranosyl)cytosine ([18F]FAC) positron emissio… Show more
“…Abbreviations ADM: Adriamycin; aGVHD: Acute GVHD; ALCLs: Anaplastic large-cell lymphomas; allo-HSCT: Allogeneic HSCT; AML: Acute myeloid leukemia; Ara-C: Cytosine arabinoside; ATO: Arsenic trioxide; ATRA: All-trans-retinoic acid; AP1: Activator protein 1; APL: Acute promyelocytic leukemia; ATL: Adult T cell In vitro Inhibits HMGB1-induced autophagy and increases the sensitivity of leukemia cells to chemotherapy [175] mAb (2G7) In vivo Improves arthritis, LN and drug-induced liver injury [176][177][178] s-RAGE In vivo Blocks the HMGB1-RAGE signaling pathway [179] HMGB1 A-box In vitro Inhibits the proinflammatory actions of the B-box [5] TAT-HMGB1A In vitro Reduces secretion of endogenous HMGB1 protein [180] GL Decreases serum HMGB1 levels and improves SIRS in hematological malignancies; improves DIC in AML; inhibits HMGB1 protein secretion and inhibits I-κB phosphorylation [190][191][192]…”
Section: Discussionmentioning
confidence: 99%
“…Several anti-HMGB1 monoclonal antibodies have been developed for clinical applications. The monoclonal antibody 2G7 binds to the HMGB1 epitope containing aa 53-63 and has shown beneficial therapeutic effects in experimental models of arthritis, lupus nephritis (LN) and drug-induced liver injury [176][177][178].…”
High mobility group box 1 (HMGB1) is a nonhistone chromatin-associated protein that has been widely reported to play a pivotal role in the pathogenesis of hematopoietic malignancies. As a representative damage-associated molecular pattern (DAMP), HMGB1 normally exists inside cells but can be secreted into the extracellular environment through passive or active release. Extracellular HMGB1 binds with several different receptors and interactors to mediate the proliferation, differentiation, mobilization, and senescence of hematopoietic stem cells (HSCs). HMGB1 is also involved in the formation of the inflammatory bone marrow (BM) microenvironment by activating proinflammatory signaling pathways. Moreover, HMGB1-dependent autophagy induces chemotherapy resistance in leukemia and multiple myeloma. In this review, we systematically summarize the emerging roles of HMGB1 in carcinogenesis, progression, prognosis, and potential clinical applications in different hematopoietic malignancies. In summary, targeting the regulation of HMGB1 activity in HSCs and the BM microenvironment is highly beneficial in the diagnosis and treatment of various hematopoietic malignancies.
“…Abbreviations ADM: Adriamycin; aGVHD: Acute GVHD; ALCLs: Anaplastic large-cell lymphomas; allo-HSCT: Allogeneic HSCT; AML: Acute myeloid leukemia; Ara-C: Cytosine arabinoside; ATO: Arsenic trioxide; ATRA: All-trans-retinoic acid; AP1: Activator protein 1; APL: Acute promyelocytic leukemia; ATL: Adult T cell In vitro Inhibits HMGB1-induced autophagy and increases the sensitivity of leukemia cells to chemotherapy [175] mAb (2G7) In vivo Improves arthritis, LN and drug-induced liver injury [176][177][178] s-RAGE In vivo Blocks the HMGB1-RAGE signaling pathway [179] HMGB1 A-box In vitro Inhibits the proinflammatory actions of the B-box [5] TAT-HMGB1A In vitro Reduces secretion of endogenous HMGB1 protein [180] GL Decreases serum HMGB1 levels and improves SIRS in hematological malignancies; improves DIC in AML; inhibits HMGB1 protein secretion and inhibits I-κB phosphorylation [190][191][192]…”
Section: Discussionmentioning
confidence: 99%
“…Several anti-HMGB1 monoclonal antibodies have been developed for clinical applications. The monoclonal antibody 2G7 binds to the HMGB1 epitope containing aa 53-63 and has shown beneficial therapeutic effects in experimental models of arthritis, lupus nephritis (LN) and drug-induced liver injury [176][177][178].…”
High mobility group box 1 (HMGB1) is a nonhistone chromatin-associated protein that has been widely reported to play a pivotal role in the pathogenesis of hematopoietic malignancies. As a representative damage-associated molecular pattern (DAMP), HMGB1 normally exists inside cells but can be secreted into the extracellular environment through passive or active release. Extracellular HMGB1 binds with several different receptors and interactors to mediate the proliferation, differentiation, mobilization, and senescence of hematopoietic stem cells (HSCs). HMGB1 is also involved in the formation of the inflammatory bone marrow (BM) microenvironment by activating proinflammatory signaling pathways. Moreover, HMGB1-dependent autophagy induces chemotherapy resistance in leukemia and multiple myeloma. In this review, we systematically summarize the emerging roles of HMGB1 in carcinogenesis, progression, prognosis, and potential clinical applications in different hematopoietic malignancies. In summary, targeting the regulation of HMGB1 activity in HSCs and the BM microenvironment is highly beneficial in the diagnosis and treatment of various hematopoietic malignancies.
“…TLR2 and TLR4 are expressed not only in parenchymal cells but also in infiltrating neutrophils and mononuclear phagocytes, including macrophages and dendritic cells [137]. The HMGB1 (high mobility group box 1) protein, which binds DNA and the lupus autoantigen released under inflammation, can induce the activation of NF-κB in a TLR2-dependent and TLR4-RAGE-dependent manner in mononuclear phagocytes and neutrophils [138][139][140][141][142][143] as well as in mesangial cells [144]. Mesangial cells and podocytes in humans are characterized by the expression of TLR4 [145].…”
One of the major challenges faced by modern nephrology is the identification of biomarkers associated with histopathological patterns or defined pathogenic mechanisms that may assist in the non-invasive diagnosis of kidney disease, particularly glomerulopathy. The identification of such molecules may allow prognostic subgroups to be established based on the type of disease, thereby predicting response to treatment or disease relapse. Advances in understanding the pathogenesis of diseases, such as membranous nephropathy, minimal change disease, focal segmental glomerulosclerosis, IgA (immunoglobulin A) nephropathy, and diabetic nephropathy, along with the progressive development and standardization of plasma and urine proteomics techniques, have facilitated the identification of an increasing number of molecules that may be useful for these purposes. The growing number of studies on the role of TLR (toll-like receptor) receptors in the pathogenesis of kidney disease forces contemporary researchers to reflect on these molecules, which may soon join the group of renal biomarkers and become a helpful tool in the diagnosis of glomerulopathy. In this article, we conducted a thorough review of the literature on the role of TLRs in the pathogenesis of glomerulopathy. The role of TLR receptors as potential marker molecules for the development of neoplastic diseases is emphasized more and more often, as prognostic factors in diseases on several epidemiological backgrounds.
“…It is also important to mention that the key findings related to NETs and their role in autoimmune diseases, for example, systemic lupus erythematosus (SLE) have been made in a rodent model [113][114][115]. Furthermore, it has also been shown that treatment with HMGB1 antibody inhibited the infiltration of neutrophils and, subsequently, NET formation without altering the antibody production in lupus-prone mice [116]. The antibody treatment additionally suppressed the NET manifestation in the glomerulus [116].…”
Section: Murinaementioning
confidence: 99%
“…Furthermore, it has also been shown that treatment with HMGB1 antibody inhibited the infiltration of neutrophils and, subsequently, NET formation without altering the antibody production in lupus-prone mice [116]. The antibody treatment additionally suppressed the NET manifestation in the glomerulus [116]. The detection of NETs in lesions of patients suffering from MPO-antineutrophil cytoplasmic antibody (ANCA) associated vasculitis (MPO AVV) suggested an additional role of NETs in this autoimmune condition [41].…”
The discovery, in 2004, of extracellular traps released by neutrophils has extended our understanding of the mode of action of various innate immune cells. This fascinating discovery demonstrated the extracellular trapping and killing of various pathogens by neutrophils. During the last decade, evidence has accumulated showing that extracellular traps play a crucial role in the defence mechanisms of various cell types present in vertebrates, invertebrates, and plants. The aim of this review is to summarise the relevant literature on the evolutionary history of extracellular traps used as a weapon in various kingdoms of life. Biology 2020, 9, 34 2 of 23On the basis of findings from several studies mostly performed with human and murine neutrophils, the following three different pathways that lead to the formation of ETs by innate immune cells have been identified: (1) Release of nuclear DNA by ETosis, a suicidal cell death associated with the rupture of the nuclear membrane prior to cell lysis [14,15]; (2) vesicular release of nuclear DNA by viable cells [16,17]; and (3) release of mitochondrial DNA [18,19]. However, the exact molecular mechanisms leading to one or the other phenotype of ET formation has still not been entirely clarified. A group of renowned scientists and experts on NETs has recently published an opinionated review on the subject due to the abundance of available data that has also led to some confusion in the NET/ET research community because of contradictory results and divergent scientific concepts, for example, the molecular pathways of ET formation or the origin of the DNA that forms the ET scaffold [20]. There is a strong consensus about the composition of ETs among the findings that NETs contain a high amount of granule proteins, for example, cell-type-specific proteases and other antibacterial molecules that are associated with DNA-histone complexes. However, it is still unclear how different triggers or pathways have led to phenotypical differences about the source of DNA or viability of the ET-releasing cell.Comparison of ET phenotypical differences between host species in relation to evolutionary aspects, especially by comparing data from phylogenetic groups, would help to understand the pathways of ET formation in more detail.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.