Cytokine synthesis and release is an essential component of the innate immune system, but inappropriate, excessive production results in a generalized systemic inflammatory response which damages ...distant organs. Recent research has identified an immunomodulatory function of the vagus nerve whereby activation of the efferent arm results in regulation of cytokine production. Termed the ‘cholinergic anti-inflammatory pathway’, this neuro-immune communication provides the host with a fast, discrete, and localized means of controlling the immune response and preventing excessive inflammation. Stimulation of the vagus nerve attenuates cytokine production and improves survival in experimental sepsis, haemorrhagic shock, ischaemia–reperfusion injury, and other conditions of cytokine excess and research is now underway in developing new and novel therapeutics aimed at stimulating the vagus nerve either directly or targeting specific components of the pathway.
Renal Inflammation and Fibrosis: A Double-edged Sword Black, Laurence M.; Lever, Jeremie M.; Agarwal, Anupam
Journal of Histochemistry & Cytochemistry,
09/2019, Letnik:
67, Številka:
9
Book Review, Journal Article
Recenzirano
Odprti dostop
Renal tissue injury initiates inflammatory and fibrotic processes that occur to promote regeneration and repair. After renal injury, damaged tissue releases cytokines and chemokines, which stimulate ...activation and infiltration of inflammatory cells to the kidney. Normal tissue repair processes occur simultaneously with activation of myofibroblasts, collagen deposition, and wound healing responses; however, prolonged activation of pro-inflammatory and pro-fibrotic cell types causes excess extracellular matrix deposition. This review focuses on the physiological and pathophysiological roles of specialized cell types, cytokines/chemokines, and growth factors, and their implications in recovery or exacerbation of acute kidney injury.
Acute gouty arthritis is caused by endogenously formed monosodium urate (MSU) crystals, which are potent activators of the NLRP3 inflammasome. However, to induce the release of active interleukin ...(IL)-1β, an additional stimulus is needed. Saturated long-chain free fatty acids (FFAs) can provide such a signal and stimulate transcription of pro-IL-1β. In contrast, the short-chain fatty acid butyrate possesses anti-inflammatory effects. One of the mechanisms involved is inhibition of histone deacetylases (HDACs). Here, we explored the effects of butyrate on MSU+FFA-induced cytokine production and its inhibition of specific HDACs.
Freshly isolated peripheral blood mononuclear cells (PBMCs) from healthy donors were stimulated with MSU and palmitic acid (C16.0) in the presence or absence of butyrate or a synthetic HDAC inhibitor. Cytokine responses were measured with ELISA and quantitative PCR. HDAC activity was measured with fluorimetric assays.
Butyrate decreased C16.0+MSU-induced production of IL-1β, IL-6, IL-8 and IL-1β mRNA in PBMCs from healthy donors. Similar results were obtained in PBMCs isolated from patients with gout. Butyrate specifically inhibited class I HDACs. The HDAC inhibitor, panobinostat and the potent HDAC inhibitor, ITF-B, also decreased ex vivo C16.0+MSU-induced IL-1β production.
In agreement with the reported low inhibitory potency of butyrate, a high concentration was needed for cytokine suppression, whereas synthetic HDAC inhibitors showed potent anti-inflammatory effects at nanomolar concentrations. These novel HDAC inhibitors could be effective in the treatment of acute gout. Moreover, the use of specific HDAC inhibitors could even improve the efficacy and reduce any potential adverse effects.
Mesenchymal stromal cells (MSCs) are multipotent cells, immunomodulatory stem cells that are currently used for regenerative medicine and treatment of a number of inflammatory diseases, thanks to ...their ability to significantly influence tissue microenvironments through the secretion of large variety of soluble factors. Recently, several groups have reported the presence of extracellular vesicles (EVs) within MSC secretoma, showing their beneficial effect in different animal models of disease. Here, we used a standardized methodological approach to dissect the immunomodulatory effects exerted by MSC-derived EVs on unfractionated peripheral blood mononuclear cells and purified T, B and NK cells. We describe here for the first time: i. direct correlation between the degree of EV-mediated immunosuppression and EV uptake by immune effector cells, a phenomenon further amplified following MSC priming with inflammatory cytokines; ii. induction in resting MSCs of immunosuppressive properties towards T cell proliferation through EVs obtained from primed MSCs, without any direct inhibitory effect towards T cell division. Our conclusion is that the use of reproducible and validated assays is not only useful to characterize the mechanisms of action of MSC-derived EVs, but is also capable of justifying EV potential use as alternative cell-free therapy for the treatment of human inflammatory diseases.
Abstract
Introduction:
Sleep fragmentation (SF) occurs in many disease states and frequently occurs in both the pediatric and adult intensive care units. However, it is unclear how sleep ...fragmentation in the absence of disease effects the neurochemical and behavioral development of the brain. In adults, SF results in daytime somnolence and a reduction in performance in attentional and vigilance tasks. Rodents who experience SF exhibit transient microglial activation and impaired hippocampal learning. The effects of SF on microglial activation and cytokine expression on the developing brain and long-term neurocognitive consequences have not been studied.
Methods:
Post-natal day 3 New Zealand White rabbit kits were assigned to one of three conditions: SF, sham, and control. The SF group was placed on an orbital shaker controlled by a timer to induce repetitive on/off cycling set at 100rpm on a 120s cycle (30s on, 90s off) for 72 hours. Shams were placed in an incubator for 72 hours, while the control group remained with the dam. Open field and behavioral milestone testing occurred before, during, and after active fragmentation. Fourteen days after fragmentation kits were challenged with a novel object recognition task. Three weeks after SF, a spontaneous alternation T-maze task was performed. Kits were sacrificed 3–50 days after the last day of fragmentation. Each hemisphere was processed separately for immunohistochemical evaluation and cytokine expression using rt-PCR.
Results:
Microglial activation was associated with region specific modulations in cytokine production, and an upregulation of indoleamine 2,3-dioxygenase. Microglia continued to be activated in the SF group 50-days post-fragmentation. During active fragmentation and up to 24-hours post-fragmentation, SF kits displayed a hyperactive phenotype, with a higher velocity and traveled more distance in the open field. Long term, SF resulted in impaired novel object recognition and spent significantly more time completing the T-maze task.
Conclusion:
Early sleep fragmentation may lead to chronic immune dysregulation in the immature brain, subsequently leading to diminished long-term performance in cognitive tasks.
Support (If Any):
HL110952-03, Society for Anesthesia and Sleep Medicine Research Grant.
Abstract
Introduction:
Growing evidence has shown that Qigong exercise improves sleep quality and alleviates depressive symptoms. However, the mechanisms underlying the effects of Qigong exercise ...remain unclear.
Methods:
A randomized waitlist-controlled trial was conducted to assess efficacy of Qigong exercise and investigate relationship between pro-inflammatory cytokines and self-reported symptoms among depressed persons with sleep disturbance. 173 participants were screened and recruited from the community. Intervention was eight 3-hour weekly sessions of Qigong training plus 30-minute self-practice at least 3 times per week. Self-reported questionnaires, including Pittsburgh Sleep Quality Index (PSQI), Center for Epidemiologic Studies Depression Scale (CES-D) and perceived stress scale (PSS) and measurement of pro-inflammatory cytokines interleukin (IL)-1β and IL-6 were assessed at baseline (T0), immediate post-intervention (T1) and 3-month post-intervention (T2).
Results:
Compared with waitlist control group, independent t-tests showed that Qigong exercise significantly improved sleep quality and reduced depressive symptoms and perceived stress as measured by PSQI (-1.7 vs -0.7, p =.014), CES-D and PSS and lowered IL-6 (-0.21 vs 0.70, P = <.001) and IL-1β (-0.08 vs 0.00, P = .002) at T1. Significant association was found between PSQI change score and reduction in IL-1β level at both T1 and T2 following Qigong exercise, but not with IL-6 level; while reduction in IL-6 was significantly associated with changes in CES-D and PSS scores.
Conclusion:
Qigong exercise alleviated sleep disturbance and depressive symptoms, and also reduced the levels of IL-1β and IL-6. Significant associations between reduction in IL-1β and sleep improvement were found following Qigong exercise. This study sheds light on possible underlying mechanism of regulating sleep by lowering the level of IL-1β. Further studies using polysomnography for recording NREM and REM sleep are warranted to confirm our preliminary findings.
Support (If Any):
The Centre on Behavioral Health Research Fund of the University of Hong Kong
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection has been linked to a higher risk of mortality compared to influenza, which is mainly due to severe secondary diseases, such as ...acute respiratory distress syndrome (ARDS). In turn, ARDS is characterized by an acute inflammation and an excessive activity of the coagulation cascade, rising the vulnerability for venous thromboembolic events. In order to investigate the relation of inflammation and the influence of coagulation factors on their release, human peripheral mononuclear blood cells (PBMCs) were treated with autologous serum, heparinized plasma and different doses of fibrin. Thereafter, the concentration of pro-inflammatory cytokines and chemokines in the secretome of PBMCs was measured by enzyme-linked immunosorbent assay. Our analyses revealed autologous serum to significantly increase the secretion of cytokines and chemokines after 24 h of incubation time. Furthermore, the addition of fibrin markedly increased the secretion of cytokines and chemokines by PBMCs in a dose-dependent manner. Consequently, in accordance with previous studies, our study outlines that anti-coagulation may constitute a promising tool for the treatment of SARS-CoV-2, reducing both, the cytokine storm, as well as the risk for thrombotic complications.
Phloretin, which can be isolated from apple trees, has demonstrable anti-inflammatory and anti-oxidant effects in macrophages. We previously reported that phloretin could inhibit the inflammatory ...response and reduce intercellular adhesion molecule 1 (ICAM-1) expression in interleukin (IL)-1β-activated human lung epithelial cells. In the present study we now evaluate whether phloretin exposure could ameliorate lipopolysaccharide (LPS)-induced acute lung injury in mice. Intra-peritoneal injections of phloretin were administered to mice for 7 consecutive days, prior to the induction of lung injury by intra-tracheal administration of LPS. Our subsequent analyses demonstrated that phloretin could significantly suppress LPS-induced neutrophil infiltration of lung tissue, and reduce the levels of IL-6 and tumor necrosis factor (TNF)-α in serum and bronchoalveolar lavage fluid. We also found that phloretin modulated myeloperoxidase activity and superoxide dismutase activity, with decreased gene expression levels for chemokines, proinflammatory cytokines, and ICAM-1 in inflamed lung tissue. Phloretin also significantly reduced the phosphorylation of nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK), thus limiting the inflammatory response, while promoting expression of heme oxygenase (HO)-1 and nuclear factor erythroid 2-related factor 2, both of which are cytoprotective. Our findings suggest that, mechanistically, phloretin attenuates the inflammatory and oxidative stress pathways that accompany lung injury in mice via blockade of the NF-κB and MAPK pathways.
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•Phloretin suppressed neutrophil infiltration in a murine model of acute lung injury•Phloretin decreased gene expression of proinflammatory cytokines and chemokines•Phloretin inhibited both the NF-κB and MAPK pathways in lung tissue.•Phloretin induced expression of the cytoprotective antioxidant, HO-1.
SARS-CoV-2 is a single stranded RNA (ssRNA) virus and contains GU-rich sequences distributed abundantly in the genome. In COVID-19, the infection and immune hyperactivation causes accumulation of ...inflammatory immune cells, blood clots, and protein aggregates in lung fluid, increased lung alveolar wall thickness, and upregulation of serum cytokine levels. A serum protein called serum amyloid P (SAP) has a calming effect on the innate immune system and shows efficacy as a therapeutic for fibrosis in animal models and clinical trials. Here we show that aspiration of the GU-rich ssRNA oligonucleotide ORN06 into mouse lungs induces all of the above COVID-19-like symptoms. Men tend to have more severe COVID-19 symptoms than women, and in the aspirated ORN06 model, male mice tended to have more severe symptoms than female mice. Intraperitoneal injections of SAP starting from day 1 post ORN06 aspiration attenuated the ORN06-induced increase in the number of inflammatory cells and formation of clot-like aggregates in the mouse lung fluid, reduced ORN06-increased alveolar wall thickness and accumulation of exudates in the alveolar airspace, and attenuated an ORN06-induced upregulation of the inflammatory cytokines IL-1β, IL-6, IL-12p70, IL-23, and IL-27 in serum. SAP also reduced D-dimer levels in the lung fluid. In human peripheral blood mononuclear cells, SAP attenuated ORN06-induced extracellular accumulation of IL-6. Together, these results suggest that aspiration of ORN06 is a simple model for both COVID-19 as well as cytokine storm in general, and that SAP is a potential therapeutic for diseases with COVID-19-like symptoms and/or a cytokine storm.
The outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has posed great threat to human health. T cells play a critical role in ...antiviral immunity but their numbers and functional state in COVID-19 patients remain largely unclear.
We retrospectively reviewed the counts of T cells and serum cytokine concentration from data of 522 patients with laboratory-confirmed COVID-19 and 40 healthy controls. In addition, the expression of T cell exhaustion markers were measured in 14 COVID-19 cases.
The number of total T cells, CD4
and CD8
T cells were dramatically reduced in COVID-19 patients, especially in patients requiring Intensive Care Unit (ICU) care. Counts of total T cells, CD8
T cells or CD4
T cells lower than 800, 300, or 400/μL, respectively, were negatively correlated with patient survival. T cell numbers were negatively correlated to serum IL-6, IL-10, and TNF-α concentration, with patients in the disease resolution period showing reduced IL-6, IL-10, and TNF-α concentrations and restored T cell counts. T cells from COVID-19 patients had significantly higher levels of the exhausted marker PD-1. Increasing PD-1 and Tim-3 expression on T cells was seen as patients progressed from prodromal to overtly symptomatic stages.
T cell counts are reduced significantly in COVID-19 patients, and the surviving T cells appear functionally exhausted. Non-ICU patients with total T cells counts lower than 800/μL may still require urgent intervention, even in the immediate absence of more severe symptoms due to a high risk for further deterioration in condition.
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