scholarly journals Deubiquitinases: Novel Therapeutic Targets in Immune Surveillance?

2016 ◽  
Vol 2016 ◽  
pp. 1-13 ◽  
Author(s):  
Gloria Lopez-Castejon ◽  
Mariola J. Edelmann
Keyword(s):  
Small Molecules ◽  
Tissue Injury ◽  
Immune Surveillance ◽  
Therapeutic Targets ◽  
Inflammasome Activation ◽  
Ubiquitin System ◽  
Molecular Pattern ◽  
Molecular Patterns ◽  
Potential Use

Inflammation is a protective response of the organism to tissue injury or infection. It occurs when the immune system recognizes Pathogen-Associated Molecular Patterns (PAMPs) or Damage-Associated Molecular Pattern (DAMPs) through the activation of Pattern Recognition Receptors. This initiates a variety of signalling events that conclude in the upregulation of proinflammatory molecules, which initiate an appropriate immune response. This response is tightly regulated since any aberrant activation of immune responses would have severe pathological consequences such as sepsis or chronic inflammatory and autoimmune diseases. Accumulative evidence shows that the ubiquitin system, and in particular ubiquitin-specific isopeptidases also known as deubiquitinases (DUBs), plays crucial roles in the control of these immune pathways. In this review we will give an up-to-date overview on the role of DUBs in the NF-κB pathway and inflammasome activation, two intrinsically related events triggered by activation of the membrane TLRs as well as the cytosolic NOD and NLR receptors. Modulation of DUB activity by small molecules has been proposed as a way to control dysregulation or overactivation of these key players of the inflammatory response. We will also discuss the advances and challenges of a potential use of DUBs as therapeutic targets in inflammatory pathologies.

The Role of High Mobility Group Box 1 (HMGB1) in Neurodegeneration: A Systematic Review

2022 ◽  
Vol 20 ◽  
Author(s):  
Fathimath Zaha Ikram ◽  
Alina Arulsamy ◽  
Thaarvena Retinasamy ◽  
Mohd. Farooq Shaikh
Keyword(s):  
Systematic Review ◽  
Tissue Injury ◽  
High Mobility ◽  
High Mobility Group ◽  
Hmgb1 Protein ◽  
Toll Like Receptor 4 ◽  
Neuroinflammatory Response ◽  
Molecular Pattern ◽  
Glycation End Products

Background: High mobility group box 1 (HMGB1) protein is a damage-associated molecular pattern (DAMP) molecule that plays an important role in the repair and regeneration of tissue injury. It also acts as a pro-inflammatory cytokine through the activation of toll-like receptor 4 (TLR4) and receptor for advanced glycation end products (RAGE), to elicit the neuroinflammatory response. HMGB1 may aggravate several cellular responses which may lead to pathological inflammation and cellular death. Thus, there have been a considerable amount of research into the pathological role of HMGB1 in diseases. However, whether the mechanism of action of HMGB1 is similar in all neurodegenerative disease pathology remains to be determined. Objective: Therefore, this systematic review aimed to critically evaluate and elucidate the role of HMGB1 in the pathology of neurodegeneration based on the available literature. Methods: A comprehensive literature search was performed on four databases; EMBASE, PubMed, Scopus, and CINAHL Plus. Results: A total of 85 articles were selected for critical appraisal, after subjecting to the inclusion and exclusion criteria in this study. The selected articles revealed that HMGB1 levels were found elevated in most neurodegeneration except in Huntington’s disease and Spinocerebellar ataxia, where the levels were found decreased. This review also showcased that HMGB1 may act on distinctive pathways to elicit its pathological response leading to the various neurodegeneration processes/diseases. Conclusion: While there have been promising findings in HMGB1 intervention research, further studies may still be required before any HMGB1 intervention may be recommended as a therapeutic target for neurodegenerative diseases.

scholarly journals The Role of Toll-Like Receptor 4 in Infectious and Noninfectious Inflammation

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Monica Molteni ◽  
Sabrina Gemma ◽  
Carlo Rossetti
Keyword(s):  
Tissue Injury ◽  
Sterile Inflammation ◽  
Research Progress ◽  
Toll Like Receptor ◽  
Proinflammatory Response ◽  
Toll Like Receptor 4 ◽  
The Family ◽  
Tlr4 Activation ◽  
Molecular Patterns

Toll-like receptor 4 (TLR4) belongs to the family of pattern recognition receptors (PRRs). They are highly conserved receptors that recognize conserved pathogen-associated molecular patterns (PAMPs), thus representing the first line of defense against infections. TLR4 has been long recognized as the sensing receptor for gram-negative lipopolysaccharide (LPS). In addition, it also binds endogenous molecules produced as a result of tissue injury. Hence, TLR4 represents a key receptor on which both infectious and noninfectious stimuli converge to induce a proinflammatory response. TLR4-mediated inflammation, triggered by exogenous or endogenous ligands, is also involved in several acute and chronic diseases, having a pivotal role as amplifier of the inflammatory response. This review focuses on the research progress about the role of TLR4 activation in infectious and noninfectious (e.g., sterile) inflammation and the effects of TLR4 signaling in some pathological conditions.

scholarly journals Macrophage Uptake of Necrotic Cell DNA Activates the AIM2 Inflammasome to Regulate a Proinflammatory Phenotype in CKD

2018 ◽  
Vol 29 (4) ◽  
pp. 1165-1181 ◽  
Author(s):  
Takanori Komada ◽  
Hyunjae Chung ◽  
Arthur Lau ◽  
Jaye M. Platnich ◽  
Paul L. Beck ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Inflammasome Activation ◽  
Dna Uptake ◽  
Chronic Injury ◽  
Caspase 1 ◽  
Double Stranded Dna ◽  
Molecular Pattern ◽  
Macrophage Uptake

Nonmicrobial inflammation contributes to CKD progression and fibrosis. Absent in melanoma 2 (AIM2) is an inflammasome-forming receptor for double-stranded DNA. AIM2 is expressed in the kidney and activated mainly by macrophages. We investigated the potential pathogenic role of the AIM2 inflammasome in kidney disease. In kidneys from patients with diabetic or nondiabetic CKD, immunofluorescence showed AIM2 expression in glomeruli, tubules, and infiltrating leukocytes. In a mouse model of unilateral ureteral obstruction (UUO), Aim2 deficiency attenuated the renal injury, fibrosis, and inflammation observed in wild-type (WT) littermates. In bone marrow chimera studies, UUO induced substantially more tubular injury and IL-1β cleavage in Aim2−/− or WT mice that received WT bone marrow than in WT mice that received Aim2−/− bone marrow. Intravital microscopy of the kidney in LysM(gfp/gfp) mice 5–6 days after UUO demonstrated the significant recruitment of GFP+ proinflammatory macrophages that crawled along injured tubules, engulfed DNA from necrotic cells, and expressed active caspase-1. DNA uptake occurred in large vacuolar structures within recruited macrophages but not resident CX3CR1+ renal phagocytes. In vitro, macrophages that engulfed necrotic debris showed AIM2-dependent activation of caspase-1 and IL-1β, as well as the formation of AIM2+ ASC specks. ASC specks are a hallmark of inflammasome activation. Cotreatment with DNaseI attenuated the increase in IL-1β levels, confirming that DNA was the principal damage-associated molecular pattern in this process. Therefore, the activation of the AIM2 inflammasome by DNA from necrotic cells drives a proinflammatory phenotype that contributes to chronic injury in the kidney.

scholarly journals Constitutive and stimulated macropinocytosis in macrophages: roles in immunity and in the pathogenesis of atherosclerosis

2018 ◽  
Vol 374 (1765) ◽  
pp. 20180147 ◽  
Author(s):  
Sasha A. Doodnauth ◽  
Sergio Grinstein ◽  
Michelle E. Maxson
Keyword(s):  
Foam Cell ◽  
Oxidized Ldl ◽  
Low Density Lipoprotein ◽  
Immune Surveillance ◽  
Density Lipoprotein ◽  
Unique Type ◽  
Functional Roles ◽  
Fluid Uptake ◽  
Molecular Patterns

Macrophages respond to several stimuli by forming florid membrane ruffles that lead to fluid uptake by macropinocytosis. This type of induced macropinocytosis, executed by a variety of non-malignant and malignant cells, is initiated by transmembrane receptors and is involved in nutrient acquisition and mTOR signalling. However, macrophages also perform a unique type of constitutive ruffling and macropinocytosis that is dependent on the presence of extracellular calcium. Calcium-sensing receptors are responsible for this activity. This distinct form of macropinocytosis enables macrophages to continuously sample their microenvironment for antigenic molecules and for pathogen- and danger-associated molecular patterns, as part of their immune surveillance functions. Interestingly, even within the monocyte lineage, there are differences in macropinocytic ability that reflect the polarized functional roles of distinct macrophage subsets. This review discusses the shared and distinct features of both induced and constitutive macropinocytosis displayed by the macrophage lineage and their roles in physiology, immunity and pathophysiology. In particular, we analyse the role of macropinocytosis in the uptake of modified low-density lipoprotein (LDL) and its contribution to foam cell and atherosclerotic plaque formation. We propose a combined role of scavenger receptors and constitutive macropinocytosis in oxidized LDL uptake, a process we have termed ‘receptor-assisted macropinocytosis'. This article is part of the Theo Murphy meeting issue ‘Macropinocytosis’.

scholarly journals Inflammation and Liver Cancer: Molecular Mechanisms and Therapeutic Targets

2019 ◽  
Vol 39 (01) ◽  
pp. 026-042 ◽  
Author(s):  
Yoon Yang ◽  
So Kim ◽  
Ekihiro Seki
Keyword(s):  
Adaptive Immunity ◽  
Molecular Mechanisms ◽  
Immune Surveillance ◽  
Therapeutic Targets ◽  
Nonalcoholic Fatty Liver ◽  
Adaptive Immune Cells ◽  
Early Hcc ◽  
Nonalcoholic Fatty Liver Diseases ◽  
Factor Α

AbstractHepatocellular carcinoma (HCC) is associated with chronic inflammation and fibrosis arising from different etiologies, including hepatitis B and C and alcoholic and nonalcoholic fatty liver diseases. The inflammatory cytokines tumor necrosis factor-α and interleukin-6 and their downstream targets nuclear factor kappa B (NF-κB), c-Jun N-terminal kinase (JNK), and signal transducer and activator of transcription 3 drive inflammation-associated HCC. Further, while adaptive immunity promotes immune surveillance to eradicate early HCC, adaptive immune cells, such as CD8+ T cells, Th17 cells, and B cells, can also stimulate HCC development. Thus, the role of the hepatic immune system in HCC development is a highly complex topic. This review highlights the role of cytokine signals, NF-κB, JNK, innate and adaptive immunity, and hepatic stellate cells in HCC and discusses whether these pathways could be therapeutic targets. The authors will also discuss cholangiocarcinoma and liver metastasis because biliary inflammation and tumor-associated stroma are essential for cholangiocarcinoma development and because primary tumor-derived inflammatory mediators promote the formation of a “premetastasis niche” in the liver.

Linking proximal and downstream signalling events in hepatic ischaemia/reperfusion injury

2006 ◽  
Vol 34 (5) ◽  
pp. 957-959 ◽  
Author(s):  
G. Jeyabalan ◽  
A. Tsung ◽  
T.R. Billiar
Keyword(s):  
Reperfusion Injury ◽  
Immune Surveillance ◽  
High Mobility ◽  
Intracellular Signalling ◽  
Ischaemia Reperfusion Injury ◽  
Signalling Molecules ◽  
Ischaemia Reperfusion ◽  
The Many ◽  
Molecular Patterns

Hepatic I/R (ischaemia/reperfusion) injury occurs in a variety of clinical settings including transplantation, elective liver resections and trauma. One of the challenges in studying the pathophysiology of I/R injury is the fact that the liver plays a central role in a variety of metabolic pathways in addition to governing aspects of immune surveillance and tolerance. The pathways activated in response to insults as varied as toxins, microbial and endogenous ligands and I/R may share common elements. The multiple intracellular signalling cascades involved in this process and the initiating events are still under investigation. Recent work on the role of TLRs (Toll-like receptors) in I/R injury has elucidated some of the more proximal signalling events in the pathway. In addition to the well-established role of signalling molecules such as NO (nitric oxide) in mediating damage or protection following hepatic I/R, more recent studies have focused on the participation of endogenous danger signals or DAMPs (damage-associated molecular patterns) such as HMGB1 (high-mobility group box 1). The complex interplay between HMGB1, TLRs and the many intracellular signalling molecules and pathways is illustrative of how our understanding of hepatic I/R injury is continually evolving.

scholarly journals Role of the Ubiquitin System in Chronic Pain

2021 ◽  
Vol 14 ◽  
Author(s):  
Jiurong Cheng ◽  
Yingdong Deng ◽  
Jun Zhou
Keyword(s):  
Chronic Pain ◽  
Molecular Mechanisms ◽  
Therapeutic Targets ◽  
Public Health Issue ◽  
Deubiquitinating Enzyme ◽  
Ubiquitin System ◽  
Significant Public Health ◽  
Underlying Mechanisms ◽  
Insight Into

As a significant public health issue, chronic pain, mainly neuropathic pain (NP) and inflammatory pain, has a severe impact. The underlying mechanisms of chronic pain are enigmatic at present. The roles of ubiquitin have been demonstrated in various physiological and pathological conditions and underscore its potential as therapeutic targets. The dysfunction of the component of the ubiquitin system that occurs during chronic pain is rapidly being discovered. These results provide insight into potential molecular mechanisms of chronic pain. Chronic pain is regulated by ubiquitination, SUMOylation, ubiquitin ligase, and deubiquitinating enzyme (DUB), etc. Insight into the mechanism of the ubiquitin system regulating chronic pain might contribute to relevant therapeutic targets and the development of novel analgesics.

scholarly journals Interactions between tumor-derived proteins and Toll-like receptors

2020 ◽  
Vol 52 (12) ◽  
pp. 1926-1935
Author(s):  
Gun-Young Jang ◽  
Ji won Lee ◽  
Young Seob Kim ◽  
Sung Eun Lee ◽  
Hee Dong Han ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
T Cell Activation ◽  
Immune Cells ◽  
Cell Activation ◽  
Tissue Injury ◽  
Suppressor Cells ◽  
Toll Like Receptors ◽  
Molecular Pattern ◽  
Molecular Patterns ◽  
Dying Cells

AbstractDamage-associated molecular patterns (DAMPs) are danger signals (or alarmins) alerting immune cells through pattern recognition receptors (PRRs) to begin defense activity. Moreover, DAMPs are host biomolecules that can initiate a noninflammatory response to infection, and pathogen-associated molecular pattern (PAMPs) perpetuate the inflammatory response to infection. Many DAMPs are proteins that have defined intracellular functions and are released from dying cells after tissue injury or chemo-/radiotherapy. In the tumor microenvironment, DAMPs can be ligands for Toll-like receptors (TLRs) expressed on immune cells and induce cytokine production and T-cell activation. Moreover, DAMPs released from tumor cells can directly activate tumor-expressed TLRs that induce chemoresistance, migration, invasion, and metastasis. Furthermore, DAMP-induced chronic inflammation in the tumor microenvironment causes an increase in immunosuppressive populations, such as M2 macrophages, myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs). Therefore, regulation of DAMP proteins can reduce excessive inflammation to create an immunogenic tumor microenvironment. Here, we review tumor-derived DAMP proteins as ligands of TLRs and discuss their association with immune cells, tumors, and the composition of the tumor microenvironment.

scholarly journals Autophagy in Alcohol-Induced Multiorgan Injury: Mechanisms and Potential Therapeutic Targets

2014 ◽  
Vol 2014 ◽  
pp. 1-20 ◽  
Author(s):  
Yuan Li ◽  
Shaogui Wang ◽  
Hong-Min Ni ◽  
Heqing Huang ◽  
Wen-Xing Ding
Keyword(s):  
Molecular Mechanisms ◽  
Tissue Injury ◽  
Current Knowledge ◽  
Therapeutic Targets ◽  
Degradation Pathway ◽  
Protective Mechanism ◽  
Intracellular Degradation ◽  
Injury Mechanisms ◽  
Evolutionarily Conserved

Autophagy is a genetically programmed, evolutionarily conserved intracellular degradation pathway involved in the trafficking of long-lived proteins and cellular organelles to the lysosome for degradation to maintain cellular homeostasis. Alcohol consumption leads to injury in various tissues and organs including liver, pancreas, heart, brain, and muscle. Emerging evidence suggests that autophagy is involved in alcohol-induced tissue injury. Autophagy serves as a cellular protective mechanism against alcohol-induced tissue injury in most tissues but could be detrimental in heart and muscle. This review summarizes current knowledge about the role of autophagy in alcohol-induced injury in different tissues/organs and its potential molecular mechanisms as well as possible therapeutic targets based on modulation of autophagy.

HOX genes as transcriptional and epigenetic regulators during tumorigenesis and their value as therapeutic targets

Epigenomics ◽  
2019 ◽  
Vol 11 (13) ◽  
pp. 1539-1552
Author(s):  
Ana Paço ◽  
Renata Freitas
Keyword(s):  
Tumor Suppressor Genes ◽  
Hox Genes ◽  
Therapeutic Targets ◽  
Transcriptional Regulators ◽  
Gene Products ◽  
Wide Range ◽  
History Of ◽  
Epigenetic Regulators ◽  
Potential Use

Several HOX genes are aberrantly expressed in a wide range of cancers interfering with their development and resistance to treatment. This seems to be often caused by alterations in the methylation profiles of their promoters. The role of HOX gene products in cancer is highly ‘tissue specific’, relying ultimately on their ability to regulate oncogenes or tumor-suppressor genes, directly as transcriptional regulators or indirectly interfering with the levels of epigenetic regulators. Nowadays, different strategies have been tested the use of HOX genes as therapeutic targets for cancer diagnosis and treatment. Here, we trace the history of the research concerning the involvement of HOX genes in cancer, their connection with epigenetic regulation and their potential use as therapeutic targets.

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