scholarly journals Importance of Deubiquitination in Macrophage-Mediated Viral Response and Inflammation

2020 ◽  
Vol 21 (21) ◽  
pp. 8090
Author(s):  
Roya Rasaei ◽  
Neha Sarodaya ◽  
Kye-Seong Kim ◽  
Suresh Ramakrishna ◽  
Seok-Ho Hong
Keyword(s):  
Immune Response ◽  
Small Molecule ◽  
Host Defense ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Genetic Material ◽  
Immune Signaling ◽  
Ubiquitin System ◽  
Autoimmune And Inflammatory Diseases ◽  
Molecular Patterns

Ubiquitination and deubiquitination play a fundamental role in the signaling pathways associated with innate and adaptive immune responses. Macrophages are key sentinels for the host defense, triggering antiviral and inflammatory responses against various invading pathogens. Macrophages recognize the genetic material of these pathogens as pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) through the activation of its pattern recognition receptors (PRRs), initiating the cascade of immune signaling, which leads to the production of pro- and anti-inflammatory cytokines that initiates the appropriate immune response. Macrophage-mediated immune response is highly regulated and tightly controlled by the ubiquitin system since its abnormal activation or dysregulation may result in the severe pathogenesis of numerous inflammatory and autoimmune diseases. Deubiquitinating enzymes (DUBs) play a crucial role in reversing the ubiquitination and controlling the magnitude of the immune response. During infection, pathogens manipulate the host defense system by regulating DUBs to obtain nutrients and increase proliferation. Indeed, the regulation of DUBs by small molecule inhibitors has been proposed as an excellent way to control aberrant activation of immune signaling molecules. This review is focused on the complex role of DUBs in macrophage-mediated immune response, exploring the potential use of DUBs as therapeutic targets in autoimmune and inflammatory diseases by virtue of small molecule DUB inhibitors.

scholarly journals DNA damage independent inhibition of NF-κB transcription by anthracyclines

2020 ◽  
Author(s):  
Angelo Chora ◽  
Dora Pedroso ◽  
Nadja Pejanovic ◽  
Eleni Kyriakou ◽  
Henrique Colaço ◽  
...  
Keyword(s):  
Dna Damage ◽  
Transcription Factors ◽  
Binding Sites ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Anticancer Properties ◽  
Dna Binding Sites ◽  
Immune Mediated ◽  
Life Threatening ◽  
Molecular Patterns

AbstractTranscriptional programs leading to induction of a large number of genes can be rapidly initiated by the activation of only few selected transcription factors. Upon stimulation of macrophages with microbial-associated molecular patterns (MAMPs), the activation of the nuclear factor kappa B (NF-κB) family of transcription factors triggers inflammatory responses that, left uncontrolled, can lead to excessive inflammation with life-threatening consequences for the host. Here we identify and characterize a novel effect of Anthracyclines, a class of drugs currently used as potent anticancer drugs, in the regulation of NF-κB transcriptional activity in BMDMs, in addition to the previously reported DNA damage and histone eviction. Anthracyclines, including Doxorubicin, Daunorubicin and Epirubicin, disturb the complexes formed between the NF-κB subunit RelA and its DNA binding sites, to limit NF-κB-dependent gene transcription during inflammatory responses, including of pivotal pro-inflammatory mediators such as TNF. We observed that suppression of inflammation can also be mediated by Aclarubicin, Doxorubicinone and the newly developed Dimethyl-doxorubicin, which share anticancer properties with the other Anthracyclines, but do not induce DNA damage in the tested concentrations. This novel mechanism of action of Anthracyclines, contributing to the reduction of inflammation, is thus independent of the activation of DNA damage responses and may be relevant for the development of novel strategies targeting immune-mediated inflammatory diseases.

scholarly journals β-Defensin Strengthens Antimicrobial Peritoneal Mast Cell Response

2020 ◽  
Vol 2020 ◽  
pp. 1-14 ◽  
Author(s):  
Justyna Agier ◽  
Ewa Brzezińska-Błaszczyk ◽  
Sylwia Różalska ◽  
Magdalena Wiktorska ◽  
Sebastian Wawrocki ◽  
...  
Keyword(s):  
Immune Response ◽  
Host Defense ◽  
Peritoneal Mast Cell ◽  
Pathogen Defense ◽  
Migratory Response ◽  
Mrna And Protein Expression ◽  
Molecular Patterns ◽  
Defense Molecules ◽  
Ongoing Infection ◽  
Inducible Gene

Mast cells (MCs) are engaged in the processes of host defense, primarily via the presence of receptors responsible for the detection of pathogen-associated molecular patterns (PAMPs). Since BDs are exclusively host defense molecules, and MCs can elicit the antimicrobial response, this study is aimed at determining whether BDs might be involved in MC pathogen defense. We found that defensin BD-2 significantly augments the mRNA and protein expression of Toll-like receptors (TLRs) and retinoic acid-inducible gene-I-like receptor (RLR) essential for the detection of viral molecules, i.e., TLR3, TLR7, TLR9, and RIG-I in mature tissue rat peritoneal MCs (PMCs). We established that BD-2 might stimulate PMCs to release proinflammatory and immunoregulatory mediators and to induce a migratory response. Presented data on IgE-coated PMC upon BD-2 treatment suggest that in the case of allergies, there is an enhanced MC immune response and cell influx to the site of the ongoing infection. In conclusion, our data highlight that BD-2 might strongly influence MC features and activity, mainly by strengthening their role in the inflammatory mechanisms and controlling the activity of cells participating in antimicrobial processes.

Differential gene expressions of NLRC5 signaling pathway in chicken macrophages cells response to Salmonella Enteritidisderived lipopplysaccharides stimulation

2016 ◽  
Author(s):  
Guobin Chang ◽  
Lingling Qiu ◽  
Xiangping Liu ◽  
Zhiteng Li ◽  
Wei Lu ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Host Defense ◽  
Inflammatory Responses ◽  
Cell Types ◽  
Innate Immune ◽  
Gene Expressions ◽  
Mhc I ◽  
Chicken Macrophage ◽  
Differential Gene ◽  
Molecular Patterns

As we all known, NLRC5 recognizes intracellular pathogen-associated molecular patterns (PAMPs) and provokes innate immune system. Its role in innate immune response, NF-kB activation and MHC-I expression remains controversial. In the present study, it was detected that differential gene expressions in NLRC5 signaling pathway at 2, 4, 6 and 8 hours after exposure to LPS using qRT-PCR technology, then analyzed its roles in host defense. The results showed that, comparing to control groups, the expression of NLRC5, MHC-I and IL-18 in LPS-treated groups were significantly up-regulated at 2 hours post stimulation (hps), TLR4 and NF-kB showed conspicuously up-regulated at 4 hps, while STAT1 was significantly down-regulated at 8 hps. Collectively, LPS did evoke inflammatory responses and NLRC5 may negatively regulate NF-kB and critically regulate MHC-I to control intracellular PAMPs in chicken macrophage cell line but the specific role of NLRC5 in host defense relates to cell types and species tested.

scholarly journals Inflammasomes in the urinary tract: a disease-based review

2016 ◽  
Vol 311 (4) ◽  
pp. F653-F662 ◽  
Author(s):  
J. Todd Purves ◽  
F. Monty Hughes
Keyword(s):  
Urinary Tract ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Innate Immune ◽  
Common Disease ◽  
Disease States ◽  
Tract Infections ◽  
Molecular Patterns ◽  
Made In ◽  
Lower Urinary

Inflammasomes are supramolecular structures that sense molecular patterns from pathogenic organisms or damaged cells and trigger an innate immune response, most commonly through production of the proinflammatory cytokines IL-1β and IL-18, but also through less understood mechanisms independent of these cytokines. Great strides have been made in understanding these structures and their dysfunction in various inflammatory diseases, lending new insights into urological and renal problems. From a clinical perspective, benign urinary pathology almost universally involves the inflammatory process, and understanding how inflammasomes translate etiological conditions (diabetes, obstruction, stones, urinary tract infections, etc.) into acute and chronic inflammatory responses is critical to understanding these diseases at a molecular level. To date, inflammasome components have been found in the bladder, prostate, and kidney and have been shown to be activated in response to several infectious and noninfectious insults. In this review, we summarize what is known regarding inflammasomes in both the upper and lower urinary tract and describe several common disease states where they potentially play critical roles.

scholarly journals Roles for Autophagy Proteins in Immunity and Host Defense

2018 ◽  
Vol 55 (3) ◽  
pp. 366-373 ◽  
Author(s):  
Rachel L. Kinsella ◽  
Eric M. Nehls ◽  
Christina L. Stallings
Keyword(s):  
Immune Response ◽  
Host Defense ◽  
Therapeutic Strategy ◽  
Immune Cell ◽  
Inflammatory Diseases ◽  
Chronic Inflammatory Diseases ◽  
Clear Link ◽  
Pathogenic Microbes ◽  
Pathogen Clearance ◽  
Recognition Receptor

There is a clear link between defects in autophagy and the development of autoimmune and chronic inflammatory diseases, raising interest in better understanding the roles of autophagy within the immune system. In addition, autophagy has been implicated in the immune response to infection by pathogenic microbes. As such, there are efforts currently underway to develop modulators of autophagy as a therapeutic strategy for the treatment of the autoimmune, inflammatory, and infectious diseases. In this review, we discuss the numerous roles for autophagy in immunity and how these activities are linked to disease. We highlight how autophagy affects pathogen clearance, phagocytosis, pattern recognition receptor signaling, inflammation, antigen presentation, cell death, and immune cell development and maintenance. With these diverse and extensive immune-related functions for autophagy in mind, we finish by considering the possible implications of targeting autophagy as a therapeutic strategy.

scholarly journals cGAS/STING: novel perspectives of the classic pathway

2020 ◽  
Vol 1 (1) ◽  
Author(s):  
Menghui Gao ◽  
Yuchen He ◽  
Haosheng Tang ◽  
Xiangyu Chen ◽  
Shuang Liu ◽  
...  
Keyword(s):  
Immune Response ◽  
Inflammatory Diseases ◽  
Er Stress Response ◽  
Autophagy Induction ◽  
Autoimmune And Inflammatory Diseases ◽  
Secretory Phenotype ◽  
New Perspective ◽  
Sting Pathway ◽  
Exciting Area ◽  
Cancerous Cells

Abstract Cyclic GMP-AMP (cGAMP) synthase (cGAS) is a cytosolic DNA sensor and innate immune response initiator. Binding with exogenous or endogenous nucleic acids, cGAS activates its downstream adaptor, stimulator of interferon genes (STING). STING then triggers protective immune to enable the elimination of the pathogens and the clearance of cancerous cells. Apparently, aberrantly activated by self-DNA, cGAS/STING pathway is threatening to cause autoimmune and inflammatory diseases. The effects of cGAS/STING in defenses against infection and autoimmune diseases have been well studied, still it is worthwhile to discuss the roles of cGAS/STING pathway beyond the “classical” realm of innate immunity. Recent studies have revealed its involvement in non-canonical inflammasome formation, calcium hemostasis regulation, endoplasmic reticulum (ER) stress response, perception of leaking mitochondrial DNA (mtDNA), autophagy induction, cellular senescence and senescence-associated secretory phenotype (SASP) production, providing an exciting area for future exploration. Previous studies generally focused on the function of cGAS/STING pathway in cytoplasm and immune response. In this review, we summarize the latest research of this pathway on the regulation of other physiological process and STING independent reactions to DNA in micronuclei and nuclei. Together, these studies provide a new perspective of cGAS/STING pathway in human diseases.

scholarly journals Cardiac Glycosides as Immune System Modulators

Biomolecules ◽  
2021 ◽  
Vol 11 (5) ◽  
pp. 659
Author(s):  
Jan Škubník ◽  
Vladimíra Pavlíčková ◽  
Silvie Rimpelová
Keyword(s):  
Immune Response ◽  
Anticancer Agents ◽  
Cardiac Glycosides ◽  
Immune Cell ◽  
Current Knowledge ◽  
Inflammatory Diseases ◽  
Large Area ◽  
Strongly Connected ◽  
Autoimmune And Inflammatory Diseases ◽  
Multiple Signaling

Cardiac glycosides (CGs) are natural steroid compounds occurring both in plants and animals. They are known for long as cardiotonic agents commonly used for various cardiac diseases due to inhibition of Na+/K+-ATPase (NKA) pumping activity and modulating heart muscle contractility. However, recent studies show that the portfolio of diseases potentially treatable with CGs is much broader. Currently, CGs are mostly studied as anticancer agents. Their antiproliferative properties are based on the induction of multiple signaling pathways in an NKA signalosome complex. In addition, they are strongly connected to immunogenic cell death, a complex mechanism of induction of anticancer immune response. Moreover, CGs exert various immunomodulatory effects, the foremost of which are connected with suppressing the activity of T-helper cells or modulating transcription of many immune response genes by inhibiting nuclear factor kappa B. The resulting modulations of cytokine and chemokine levels and changes in immune cell ratios could be potentially useful in treating sundry autoimmune and inflammatory diseases. This review aims to summarize current knowledge in the field of immunomodulatory properties of CGs and emphasize the large area of potential clinical use of these compounds.

scholarly journals Therapeutic regulation of the NLRP3 inflammasome in chronic inflammatory diseases

2021 ◽  
Vol 44 (1) ◽  
pp. 16-35 ◽  
Author(s):  
Jin Kyung Seok ◽  
Han Chang Kang ◽  
Yong-Yeon Cho ◽  
Hye Suk Lee ◽  
Joo Young Lee
Keyword(s):  
Pattern Recognition ◽  
Small Molecule ◽  
Nlrp3 Inflammasome ◽  
Small Molecule Inhibitors ◽  
Inflammatory Diseases ◽  
Cellular Damage ◽  
Receptor Protein ◽  
Current Status ◽  
Chronic Inflammatory Diseases ◽  
Molecular Patterns

AbstractInflammasomes are cytosolic pattern recognition receptors that recognize pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) derived from invading pathogens and damaged tissues, respectively. Upon activation, the inflammasome forms a complex containing a receptor protein, an adaptor, and an effector to induce the autocleavage and activation of procaspase-1 ultimately culminating in the maturation and secretion of IL-1β and IL-18 and pyroptosis. Inflammasome activation plays an important role in host immune responses to pathogen infections and tissue repair in response to cellular damage. The NLRP3 inflammasome is a well-characterized pattern recognition receptor and is well known for its critical role in the regulation of immunity and the development and progression of various inflammatory diseases. In this review, we summarize recent efforts to develop therapeutic applications targeting the NLRP3 inflammasome to cure and prevent chronic inflammatory diseases. This review extensively discusses NLRP3 inflammasome-related diseases and current development of small molecule inhibitors providing beneficial information on the design of therapeutic strategies for NLRP3 inflammasome-related diseases. Additionally, small molecule inhibitors are classified depending on direct or indirect targeting mechanism to describe the current status of the development of pharmacological inhibitors.

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