The Arg/N-Degron Pathway—A Potential Running Back in Fine-Tuning the Inflammatory Response?

Recognition of danger signals by a cell initiates a powerful cascade of events generally leading to inflammation. Inflammatory caspases and several other proteases become activated and subsequently cleave their target proinflammatory mediators. The irreversible nature of this process implies that the newly generated proinflammatory fragments need to be sequestered, inhibited, or degraded in order to cancel the proinflammatory program or prevent chronic inflammation. The Arg/N-degron pathway is a ubiquitin-dependent proteolytic pathway that specifically degrades protein fragments bearing N-degrons, or destabilizing residues, which are recognized by the E3 ligases of the pathway. Here, we report that the Arg/N-degron pathway selectively degrades a number of proinflammatory fragments, including some activated inflammatory caspases, contributing in tuning inflammatory processes. Partial ablation of the Arg/N-degron pathway greatly increases IL-1β secretion, indicating the importance of this ubiquitous pathway in the initiation and resolution of inflammation. Thus, we propose a model wherein the Arg/N-degron pathway participates in the control of inflammation in two ways: in the generation of inflammatory signals by the degradation of inhibitory anti-inflammatory domains and as an “off switch” for inflammatory responses through the selective degradation of proinflammatory fragments.

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Transcriptomic Data Analysis Reveals a Down-Expression of Galectin-8 in Schizophrenia Hippocampus

Brain Sciences ◽

10.3390/brainsci11080973 ◽

2021 ◽

Vol 11 (8) ◽

pp. 973

Author(s):

Maria Cristina Petralia ◽

Rosella Ciurleo ◽

Alessia Bramanti ◽

Placido Bramanti ◽

Andrea Saraceno ◽

...

Keyword(s):

Inflammatory Responses ◽

Clinical Manifestations ◽

Antipsychotic Agents ◽

Standards Of Care ◽

Specific Gene ◽

Contributing Factors ◽

Healthy Donors ◽

Dorsolateral Prefrontal ◽

Inflammatory Processes ◽

Disease Specific

Schizophrenia (SCZ) is a severe psychiatric disorder with several clinical manifestations that include cognitive dysfunction, decline in motivation, and psychosis. Current standards of care treatment with antipsychotic agents are often ineffective in controlling the disease, as only one-third of SCZ patients respond to medications. The mechanisms underlying the pathogenesis of SCZ remain elusive. It is believed that inflammatory processes may play a role as contributing factors to the etiology of SCZ. Galectins are a family of β-galactoside-binding lectins that contribute to the regulation of immune and inflammatory responses, and previous reports have shown their role in the maintenance of central nervous system (CNS) homeostasis and neuroinflammation. In the current study, we evaluated the expression levels of the galectin gene family in post-mortem samples of the hippocampus, associative striatum, and dorsolateral prefrontal cortex from SCZ patients. We found a significant downregulation of LGALS8 (Galectin-8) in the hippocampus of SCZ patients as compared to otherwise healthy donors. Interestingly, the reduction of LGALS8 was disease-specific, as no modulation was observed in the hippocampus from bipolar nor major depressive disorder (MDD) patients. Prediction analysis identified TBL1XR1, BRF2, and TAF7 as potential transcription factors controlling LGALS8 expression. In addition, MIR3681HG and MIR4296 were negatively correlated with LGALS8 expression, suggesting a role for epigenetics in the regulation of LGALS8 levels. On the other hand, no differences in the methylation levels of LGALS8 were observed between SCZ and matched control hippocampus. Finally, ontology analysis of the genes negatively correlated with LGALS8 expression identified an enrichment of the NGF-stimulated transcription pathway and of the oligodendrocyte differentiation pathway. Our study identified LGALS8 as a disease-specific gene, characterizing SCZ patients, that may in the future be exploited as a potential therapeutic target.

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Deficiency of Lipin2 Results in Enhanced NF-κB Signaling and Osteoclast Formation in RAW-D Murine Macrophages

International Journal of Molecular Sciences ◽

10.3390/ijms22062893 ◽

2021 ◽

Vol 22 (6) ◽

pp. 2893

Author(s):

Asami Watahiki ◽

Seira Hoshikawa ◽

Mitsuki Chiba ◽

Hiroshi Egusa ◽

Satoshi Fukumoto ◽

...

Keyword(s):

Molecular Mechanisms ◽

Inflammatory Responses ◽

Osteoclast Formation ◽

Fine Tuning ◽

Nuclear Accumulation ◽

Innate Immune Responses ◽

Osteoclastic Resorption ◽

Bone Disorder ◽

Proinflammatory Responses ◽

Potential Therapeutic Intervention

Lipin2 is a phosphatidate phosphatase that plays critical roles in fat homeostasis. Alterations in Lpin2, which encodes lipin2, cause the autoinflammatory bone disorder Majeed syndrome. Lipin2 limits lipopolysaccharide (LPS)-induced inflammatory responses in macrophages. However, little is known about the precise molecular mechanisms underlying its anti-inflammatory function. In this study, we attempted to elucidate the molecular link between the loss of lipin2 function and autoinflammatory bone disorder. Using a Lpin2 knockout murine macrophage cell line, we showed that lipin2 deficiency enhances innate immune responses to LPS stimulation through excessive activation of the NF-κB signaling pathway, partly because of TAK1 signaling upregulation. Lipin2 depletion also enhanced RANKL-mediated osteoclastogenesis and osteoclastic resorption activity accompanied by NFATc1 dephosphorylation and increased nuclear accumulation. These results suggest that lipin2 suppresses the development of autoinflammatory bone disorder by fine-tuning proinflammatory responses and osteoclastogenesis in macrophages. Therefore, this study provides insights into the molecular pathogenesis of monogenic autoinflammatory bone disorders and presents a potential therapeutic intervention.

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Fine-tuning autophagy: from transcriptional to posttranslational regulation

AJP Cell Physiology ◽

10.1152/ajpcell.00129.2016 ◽

2016 ◽

Vol 311 (3) ◽

pp. C351-C362 ◽

Cited By ~ 17

Author(s):

Joëlle Botti-Millet ◽

Anna Chiara Nascimbeni ◽

Nicolas Dupont ◽

Etienne Morel ◽

Patrice Codogno

Keyword(s):

Posttranslational Modifications ◽

Inflammatory Responses ◽

Chronic Inflammatory Disease ◽

Autophagic Vacuole ◽

Tissue Homeostasis ◽

Fine Tuning ◽

Eukaryotic Cells ◽

Posttranslational Regulation ◽

Atg Proteins ◽

Diabetes And Obesity

Macroautophagy (hereafter called autophagy) is a vacuolar lysosomal pathway for degradation of intracellular material in eukaryotic cells. Autophagy plays crucial roles in tissue homeostasis, in adaptation to stress situations, and in immune and inflammatory responses. Alteration of autophagy is associated with cancer, diabetes and obesity, cardiovascular disease, neurodegenerative disease, autoimmune disease, infection, and chronic inflammatory disease. Autophagy is controlled by autophagy-related (ATG) proteins that act in a coordinated manner to build up the initial autophagic vacuole named the autophagosome. It is now known that the activities of ATG proteins are modulated by posttranslational modifications such as phosphorylation, ubiquitination, and acetylation. Moreover, transcriptional and epigenetic controls are involved in the regulation of autophagy in stress situations. Here we summarize and discuss how posttranslational modifications and transcriptional and epigenetic controls regulate the involvement of autophagy in the proteostasis network.

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Butyrate and the Fine-Tuning of Colonic Homeostasis: Implication for Inflammatory Bowel Diseases

International Journal of Molecular Sciences ◽

10.3390/ijms22063061 ◽

2021 ◽

Vol 22 (6) ◽

pp. 3061

Author(s):

Naschla Gasaly ◽

Marcela A. Hermoso ◽

Martín Gotteland

Keyword(s):

Inflammatory Bowel Diseases ◽

Barrier Function ◽

Cell Types ◽

Fine Tuning ◽

Current Evidence ◽

Aryl Hydrocarbon ◽

Gut Barrier Function ◽

Bowel Diseases ◽

Inflammatory Processes ◽

Inflammatory Bowel

This review describes current evidence supporting butyrate impact in the homeostatic regulation of the digestive ecosystem in health and inflammatory bowel diseases (IBDs). Butyrate is mainly produced by bacteria from the Firmicutes phylum. It stimulates mature colonocytes and inhibits undifferentiated malignant and stem cells. Butyrate oxidation in mature colonocytes (1) produces 70–80% of their energetic requirements, (2) prevents stem cell inhibition by limiting butyrate access to crypts, and (3) consumes oxygen, generating hypoxia and maintaining luminal anaerobiosis favorable to the microbiota. Butyrate stimulates the aryl hydrocarbon receptor (AhR), the GPR41 and GPR109A receptors, and inhibits HDAC in different cell types, thus stabilizing the gut barrier function and decreasing inflammatory processes. However, some studies indicate contrary effects according to butyrate concentrations. IBD patients exhibit a lower abundance of butyrate-producing bacteria and butyrate content. Additionally, colonocyte butyrate oxidation is depressed in these subjects, lowering luminal anaerobiosis and facilitating the expansion of Enterobacteriaceae that contribute to inflammation. Accordingly, gut dysbiosis and decreased barrier function in IBD seems to be secondary to the impaired mitochondrial disturbance in colonic epithelial cells.

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Pseudane-VII Regulates LPS-Induced Neuroinflammation in Brain Microglia Cells through the Inhibition of iNOS Expression

Molecules ◽

10.3390/molecules23123196 ◽

2018 ◽

Vol 23 (12) ◽

pp. 3196 ◽

Cited By ~ 7

Author(s):

Mi Kim ◽

Inae Jung ◽

Ju Na ◽

Yujeong Lee ◽

Jaewon Lee ◽

...

Keyword(s):

Neurodegenerative Diseases ◽

Inflammatory Responses ◽

Neurological Diseases ◽

Inos Expression ◽

Nuclear Factor Kappab ◽

Nuclear Factor ◽

Ros Production ◽

Proinflammatory Mediators ◽

Cox 2 ◽

Novel Target

We previously isolated pseudane-VII from the secondary metabolites of Pseudoalteromonas sp. M2 in marine water, and demonstrated its anti-inflammatory efficacy on macrophages. However, the molecular mechanism by which pseudane-VII suppresses neuroinflammation has not yet been elucidated in brain microglia. Microglia is activated by immunological stimulation or brain injury. Activated microglia secrete proinflammatory mediators which damage neurons. Neuroinflammation appears to be associated with certain neurological diseases, including Parkinson’s disease and Alzheimer’s disease. Natural compounds that suppress microglial inflammatory responses could potentially be used to prevent neurodegenerative diseases or slow their progression. In the present study, we found that pseudane-VII suppresses neuroinflammation in lipopolysaccaride (LPS)-stimulated BV-2 microglial cells and brain. Pseudane-VII was shown to inhibit the LPS-stimulated NO, ROS production and the expression of iNOS and COX-2. To identify the signaling pathway targeted by pseudane-VII, we used western blot analysis to assess the LPS-induced phosphorylation state of p38, ERK1/2, JNK1/2, and nuclear factor-kappaB (NF-κB). We found that pseudane-VII attenuated LPS-induced phosphorylation of MAPK and NF-κB. Moreover, administration of pseudane-VII in mice significantly reduced LPS-induced iNOS expression and microglia activation in brain. Taken together, our findings suggest that pseudane-VII may represent a potential novel target for treatment for neurodegenerative diseases.

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The proteasome inhibitor Bortezomib aggravates renal ischemia-reperfusion injury

AJP Renal Physiology ◽

10.1152/ajprenal.90576.2008 ◽

2009 ◽

Vol 297 (2) ◽

pp. F451-F460 ◽

Cited By ~ 23

Author(s):

Julia M. Huber ◽

Andrea Tagwerker ◽

Dorothea Heininger ◽

Gert Mayer ◽

Alexander R. Rosenkranz ◽

...

Keyword(s):

T Cells ◽

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Renal Ischemia ◽

Reversible Inhibitor ◽

Tubular Necrosis ◽

Proinflammatory Mediators ◽

Renal Ischemia Reperfusion Injury ◽

A Cell

Bortezomib is a well-established treatment option for patients with multiple myeloma (MM). It is a selective and reversible inhibitor of the proteasome that is responsible for the degradation of many regulatory proteins that are involved in apoptosis, cell-cycle regulation, or transcription. Because patients with MM are prone to develop acute renal failure, we evaluated the influence of Bortezomib on renal ischemia-reperfusion injury (IRI). Mice were subjected to renal IRI by having the renal pedicles clamped for 30 min followed by reperfusion for 3, 24, and 48 h. Mice were either pretreated with 0.5 mg/kg body wt Bortezomib or vehicle intravenously 12 h before induction of IRI. Serum creatinine and tubular necrosis were significantly increased in Bortezomib compared with vehicle-treated mice. The inflammatory response was found to be significantly decreased in Bortezomib-treated mice as reflected by a decreased infiltration of CD4+ T cells and a significantly decreased Th1 cytokine expression in the kidneys. In contrast, apoptosis was significantly increased in kidneys of Bortezomib-treated mice compared with vehicle-treated controls. Increased numbers of TUNEL-positive cells/mm2 and increased mRNA expression of proapoptotic factors were detected in kidneys of Bortezomib-treated mice. Of note, p21, a cell senescence marker, was also significantly increased in kidneys of Bortezomib-treated mice. In summary, we provide evidence that Bortezomib worsens the outcome of renal IRI by leading to increased apoptosis of tubular cells despite decreased infiltrating T cells and proinflammatory mediators.

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Activated Platelets Induce an Anti-Inflammatory Response of Monocytes/Macrophages through Cross-Regulation of PGE2and Cytokines

Mediators of Inflammation ◽

10.1155/2017/1463216 ◽

2017 ◽

Vol 2017 ◽

pp. 1-14 ◽

Cited By ~ 24

Author(s):

Bona Linke ◽

Yannick Schreiber ◽

Bettina Picard-Willems ◽

Patrick Slattery ◽

Rolf M. Nüsing ◽

...

Keyword(s):

Inflammatory Responses ◽

Cell Types ◽

Inhibitory Effect ◽

Innate Immune ◽

Prostaglandin E ◽

Murine Bone Marrow ◽

Activated Platelets ◽

Monocytes And Macrophages ◽

Inflammatory Processes ◽

Necrosis Factor

Platelets are well known for their role in hemostasis and are also increasingly recognized for their roles in the innate immune system during inflammation and their regulation of macrophage activation. Here, we aimed to study the influence of platelets on the production of inflammatory mediators by monocytes and macrophages. Analyzing cocultures of platelets and murine bone marrow-derived macrophages or human monocytes, we found that collagen-activated platelets release high amounts of prostaglandin E2(PGE2) that leads to an increased interleukin- (IL-) 10 release and a decreased tumor necrosis factor (TNF)αsecretion out of the monocytes or macrophages. Platelet PGE2mediated the upregulation of IL-10 in both cell types via the PGE2receptor EP2. Notably, PGE2-mediated IL-10 synthesis was also mediated by EP4 in murine macrophages. Inhibition of TNFαsynthesis via EP2 and EP4, but not EP1, was mediated by IL-10, since blockade of the IL-10 receptor abolished the inhibitory effect of both receptors on TNFαrelease. This platelet-mediated cross-regulation between PGE2and cytokines reveals one mechanism how monocytes and macrophages can attenuate excessive inflammatory responses induced by activated platelets in order to limit inflammatory processes.

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Oxidative Stress, Testicular Inflammatory Pathways and Male Reproduction

International Journal of Molecular Sciences ◽

10.3390/ijms221810043 ◽

2021 ◽

Vol 22 (18) ◽

pp. 10043

Author(s):

Sulagna Dutta ◽

Pallav Sengupta ◽

Petr Slama ◽

Shubhadeep Roychoudhury

Keyword(s):

Oxidative Stress ◽

Male Infertility ◽

Reproductive Tract ◽

Inflammatory Responses ◽

Male Reproduction ◽

Male Reproductive Tract ◽

Proinflammatory Mediators ◽

Global Issue ◽

Causative Factors ◽

Infertility Patients

Inflammation is among the core causatives of male infertility. Despite male infertility being a serious global issue, “bits and pieces” of its complex etiopathology still remain missing. During inflammation, levels of proinflammatory mediators in the male reproductive tract are greater than usual. According to epidemiological research, in numerous cases of male infertility, patients suffer from acute or chronic inflammation of the genitourinary tract which typically occurs without symptoms. Inflammatory responses in the male genital system are inextricably linked to oxidative stress (OS). OS is detrimental to male fertility parameters as it causes oxidative damage to reproductive cells and intracellular components. Multifarious male infertility causative factors pave the way for impairing male reproductive functions via the common mechanisms of OS and inflammation, both of which are interlinked pathophysiological processes, and the occurrence of any one of them induces the other. Both processes may be simultaneously found in the pathogenesis of male infertility. Thus, the present article aims to explain the role of inflammation and OS in male infertility in detail, as well as to show the mechanistic pathways that link causative factors of male reproductive tract inflammation, OS induction, and oxidant-sensitive cellular cascades leading to male infertility.

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HaCaT Cells as a Reliable In Vitro Differentiation Model to Dissect the Inflammatory/Repair Response of Human Keratinocytes

Mediators of Inflammation ◽

10.1155/2017/7435621 ◽

2017 ◽

Vol 2017 ◽

pp. 1-12 ◽

Cited By ~ 43

Author(s):

Irma Colombo ◽

Enrico Sangiovanni ◽

Roberta Maggio ◽

Carlo Mattozzi ◽

Stefania Zava ◽

...

Keyword(s):

Cell Density ◽

Skin Diseases ◽

Inflammatory Responses ◽

Human Keratinocytes ◽

Suitable Model ◽

Hacat Cells ◽

Primary Human Keratinocytes ◽

Proinflammatory Mediators ◽

Cytokines And Chemokines

Cultured primary human keratinocytes are frequently employed for studies of immunological and inflammatory responses; however, interpretation of experimental data may be complicated by donor to donor variability, the relatively short culture lifetime, and variations between passages. To standardize the in vitro studies on keratinocytes, we investigated the use of HaCaT cells, a long-lived, spontaneously immortalized human keratinocyte line which is able to differentiate in vitro, as a suitable model to follow the release of inflammatory and repair mediators in response to TNFα or IL-1β. Different treatment conditions (presence or absence of serum) and differentiation stimuli (increase in cell density as a function of time in culture and elevation of extracellular calcium) were considered. ELISA and Multiplex measurement technologies were used to monitor the production of cytokines and chemokines. Taken together, the results highlight that Ca2+ concentration in the medium, cell density, and presence of serum influences at different levels the release of proinflammatory mediators by HaCaT cells. Moreover, HaCaT cells maintained in low Ca2+ medium and 80% confluent are similar to normal keratinocytes in terms of cytokine production suggesting that HaCaT cells may be a useful model to investigate anti-inflammatory interventions/therapies on skin diseases.

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Regulation of Neutrophil Degranulation and Cytokine Secretion: A Novel Model Approach Based on Linear Fitting

Journal of Immunology Research ◽

10.1155/2015/817038 ◽

2015 ◽

Vol 2015 ◽

pp. 1-15 ◽

Cited By ~ 35

Author(s):

Isabelle Naegelen ◽

Nicolas Beaume ◽

Sébastien Plançon ◽

Véronique Schenten ◽

Eric J. Tschirhart ◽

...

Keyword(s):

Time Series ◽

Inflammatory Responses ◽

Inflammatory Diseases ◽

Cytokine Secretion ◽

Human Neutrophils ◽

Cytokine Release ◽

Linear Fitting ◽

Proinflammatory Mediators ◽

The Relationship ◽

Model Approach

Neutrophils participate in the maintenance of host integrity by releasing various cytotoxic proteins during degranulation. Due to recent advances, a major role has been attributed to neutrophil-derived cytokine secretion in the initiation, exacerbation, and resolution of inflammatory responses. Because the release of neutrophil-derived products orchestrates the action of other immune cells at the infection site and, thus, can contribute to the development of chronic inflammatory diseases, we aimed to investigate in more detail the spatiotemporal regulation of neutrophil-mediated release mechanisms of proinflammatory mediators. Purified human neutrophils were stimulated for different time points with lipopolysaccharide. Cells and supernatants were analyzed by flow cytometry techniques and used to establish secretion profiles of granules and cytokines. To analyze the link between cytokine release and degranulation time series, we propose an original strategy based on linear fitting, which may be used as a guideline, to (i) define the relationship of granule proteins and cytokines secreted to the inflammatory site and (ii) investigate the spatial regulation of neutrophil cytokine release. The model approach presented here aims to predict the correlation between neutrophil-derived cytokine secretion and degranulation and may easily be extrapolated to investigate the relationship between other types of time series of functional processes.

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