scholarly journals Coronavirus induces diabetic macrophage-mediated inflammation via SETDB2

2021 ◽  
Vol 118 (38) ◽  
pp. e2101071118
Author(s):  
William J. Melvin ◽  
Christopher O. Audu ◽  
Frank M. Davis ◽  
Sriganesh B. Sharma ◽  
Amrita Joshi ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Inflammatory Cytokine ◽  
Immune Cell ◽  
Gene Promoters ◽  
Cytokine Storm ◽  
Immune Cell Population ◽  
Inflammatory Gene ◽  
Stat3 Signaling ◽  
Infection Treatment ◽  
Coronavirus Infection

COVID-19 induces a robust, extended inflammatory “cytokine storm” that contributes to an increased morbidity and mortality, particularly in patients with type 2 diabetes (T2D). Macrophages are a key innate immune cell population responsible for the cytokine storm that has been shown, in T2D, to promote excess inflammation in response to infection. Using peripheral monocytes and sera from human patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and a murine hepatitis coronavirus (MHV-A59) (an established murine model of SARS), we identified that coronavirus induces an increased Mφ-mediated inflammatory response due to a coronavirus-induced decrease in the histone methyltransferase, SETDB2. This decrease in SETDB2 upon coronavirus infection results in a decrease of the repressive trimethylation of histone 3 lysine 9 (H3K9me3) at NFkB binding sites on inflammatory gene promoters, effectively increasing inflammation. Mφs isolated from mice with a myeloid-specific deletion of SETDB2 displayed increased pathologic inflammation following coronavirus infection. Further, IFNβ directly regulates SETDB2 in Mφs via JaK1/STAT3 signaling, as blockade of this pathway altered SETDB2 and the inflammatory response to coronavirus infection. Importantly, we also found that loss of SETDB2 mediates an increased inflammatory response in diabetic Mϕs in response to coronavirus infection. Treatment of coronavirus-infected diabetic Mφs with IFNβ reversed the inflammatory cytokine production via up-regulation of SETDB2/H3K9me3 on inflammatory gene promoters. Together, these results describe a potential mechanism for the increased Mφ-mediated cytokine storm in patients with T2D in response to COVID-19 and suggest that therapeutic targeting of the IFNβ/SETDB2 axis in T2D patients may decrease pathologic inflammation associated with COVID-19.

scholarly journals Cytokine Removal and Immunomodulation in COVID-19 Severe Pulmonary Respiratory Infection

2020 ◽  
Author(s):  
Karen Courville ◽  
Norman Bustamante ◽  
Maydelin Pecchio
Keyword(s):  
Inflammatory Response ◽  
Inflammatory Cytokines ◽  
Low Dose ◽  
High Volume ◽  
Pulmonary Involvement ◽  
Lung Damage ◽  
Cytokine Storm ◽  
Time Treatment ◽  
High Volume Hemofiltration ◽  
Coronavirus Infection

Coronavirus infection produces a cytokine storm in some patients, developing a moderate to severe clinical condition that is associated to increased mortality mainly because of severe pulmonary involvement. Elevated levels of IL-6 have been found in non-survivor patients. In these patients, clearance of cytokines with extracorporeal therapies, Pulse High- Volume Hemofiltration together with adsorption columns Cytosorb, in short periods of time for 1 to 3 days, could help remove inflammatory cytokines allowing a downregulation of the inflammatory response; and, at the same time, treatment with low dose steroids, could give an opportunity for the host to reach homeostasis, decreasing lung damage and improving survival.

scholarly journals A proteomic perspective and involvement of cytokines in SARS-CoV-2 infection

2021 ◽  
Author(s):  
Sarena Banu ◽  
Mohammed M Idris ◽  
Ramakrishnan Nagaraj
Keyword(s):  
Inflammatory Response ◽  
Quantitative Proteomics ◽  
Immune Cell ◽  
Cell Trafficking ◽  
Cytokine Storm ◽  
Proteomics Analysis ◽  
Initial Infection ◽  
Clinical Observations ◽  
Normal Individuals ◽  
Oropharyngeal Swab

Infection with the SARS-CoV-2 virus results in manifestation of several clinical observations from asymptomatic to multi-organ failure. Biochemically, the serious effects are due to what is described as cytokine storm. The initial infection region for COVID-19 is the nasopharyngeal/oropharyngeal region which is the site where samples are taken to examine the presence of virus. We have earlier shown that several defensin genes are down regulated in cells from this region in patients who tested positive in the RTPCR test. We have now carried out detailed proteomic analysis of the nasopharyngeal/oropharyngeal swab samples collected from normal individuals and those tested positive for SARS-CoV-2 by RTPCR, involving high throughput quantitative proteomics analysis. Several proteins like annexins, cytokines and histones were found differentially regulated in the host human cells following SARS-CoV-2 infection. Genes for these proteins were also observed to be differentially regulated when their expression was analyzed. Majority of the cytokine proteins were found to be up regulated in the infected individuals. Cell to Cell signaling interaction, Immune cell trafficking and inflammatory response pathways were found associated with the differentially regulated proteins based on network pathway analysis.

scholarly journals Immunotherapy Summary for Cytokine Storm in COVID-19

2021 ◽  
Vol 12 ◽  
Author(s):  
Yaqun Li ◽  
Wenjie Zhao ◽  
Jinhua Liu ◽  
Zichao Chen ◽  
Qingtao Lv ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Cell Activation ◽  
Immune Cell ◽  
Effective Means ◽  
Clinical Effectiveness ◽  
The Body ◽  
Cytokine Storm ◽  
Immune Cell Activation ◽  
Novel Coronavirus ◽  
Immune Imbalance

COVID-19 pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has ravaged the world, resulting in an alarming number of infections and deaths, and the number continues to increase. The pathogenesis caused by the novel coronavirus was found to be a disruption of the pro-inflammatory/anti-inflammatory response. Due to the lack of effective treatments, different strategies and treatment methods are still being researched, with the use of vaccines to make the body immune becoming the most effective means of prevention. Antiviral drugs and respiratory support are often used clinically as needed, but are not yet sufficient to alleviate the cytokine storm (CS) and systemic inflammatory response syndrome. How to neutralize the cytokine storm and inhibit excessive immune cell activation becomes the key to treating neocoronavirus pneumonia. Immunotherapy through the application of hormones and monoclonal antibodies can alleviate the immune imbalance, but the clinical effectiveness and side effects remain controversial. This article reviews the pathogenesis of neocoronavirus pneumonia and discusses the immunomodulatory therapies currently applied to COVID-19. We aim to give some conceptual thought to the prevention and immunotherapy of neocoronavirus pneumonia.

scholarly journals Glycyrrhizin Attenuates Salmonella Typhimurium-Induced Tissue Injury, Inflammatory Response, and Intestinal Dysbiosis in C57BL/6 Mice

2021 ◽  
Vol 8 ◽  
Author(s):  
Baikui Wang ◽  
Xiaolin Ye ◽  
Yuanhao Zhou ◽  
Pengwei Zhao ◽  
Yulong Mao
Keyword(s):  
Inflammatory Response ◽  
Foodborne Pathogens ◽  
Inflammatory Cytokine ◽  
Tissue Injury ◽  
Intestinal Microbes ◽  
Infection Treatment ◽  
Intestinal Dysbiosis ◽  
Tnf Α ◽  
Ifn Γ ◽  
Anti Inflammatory

Salmonellae are one of the most important foodborne pathogens, which threaten the health of humans and animals severely. Glycyrrhizin (GL) has been proven to exhibit anti-inflammatory and tissue-protective properties. Here, we investigated the effects of GL on tissue injury, inflammatory response, and intestinal dysbiosis in Salmonella Typhimurium-infected mice. Results showed that GL or gentamicin (GM) significantly (P < 0.05) alleviated ST-induced splenomegaly indicated by the decreased spleen index, injury of liver and jejunum indicated by the decreased hepatocytic apoptosis, and the increased jejunal villous height. GL significantly (P < 0.05) increased secretion of inflammatory cytokines (IFN-γ, IL-12p70, IL-6, and IL-10) in spleen and IL-12p40 mRNA expression in liver. Meanwhile, GL or GM pre-infection treatments significantly (P < 0.05) decreased ST-induced pro-inflammatory cytokine (IFN-γ, TNF-α, and IL-6) expression in both spleen and liver and increased (P < 0.05) anti-inflammatory cytokine IL-10 secretion in spleen. Furthermore, GL or GM pre-infection treatment also regulates the diversities and compositions of intestinal microbiota and decreased the negative connection among the intestinal microbes in ST-infected mice. The above findings indicate that GL alleviates ST-induced splenomegaly, hepatocytic apoptosis, injury of jejunum and liver, inflammatory response of liver and spleen, and intestinal dysbacteriosis in mice.

scholarly journals Immune Pathogenesis of COVID-19 Intoxication: Storm or Silence?

2020 ◽  
Vol 13 (8) ◽  
pp. 166
Author(s):  
Mikhail Kiselevskiy ◽  
Irina Shubina ◽  
Irina Chikileva ◽  
Suria Sitdikova ◽  
Igor Samoylenko ◽  
...  
Keyword(s):  
Immune System ◽  
Inflammatory Response ◽  
Treatment Strategy ◽  
Secondary Infection ◽  
Significant Problem ◽  
Cytokine Storm ◽  
Immune Pathogenesis ◽  
Immune Mediated ◽  
Coronavirus Infection ◽  
Excessive Inflammatory Response

Dysregulation of the immune system undoubtedly plays an important and, perhaps, determining role in the COVID-19 pathogenesis. While the main treatment of the COVID-19 intoxication is focused on neutralizing the excessive inflammatory response, it is worth considering an equally significant problem of the immunosuppressive conditions including immuno-paralysis, which lead to the secondary infection. Therefore, choosing a treatment strategy for the immune-mediated complications of coronavirus infection, one has to pass between Scylla and Charybdis, so that, in the fight against the “cytokine storm,” it is vital not to miss the point of the immune silence that turns into immuno-paralysis.

scholarly journals SHP2 inhibitor PHPS1 ameliorates acute kidney injury by Erk1/2-STAT3 signaling in a hemorrhage followed CLP mice model

2020 ◽  
Author(s):  
Jihong Jiang ◽  
Baoji Hu ◽  
Chun-Shiang Chung ◽  
Yaping Chen ◽  
Yunhe Zhang ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Inflammatory Cytokine ◽  
Immune Cell ◽  
Protective Action ◽  
Cecal Ligation ◽  
Hypovolemic Shock ◽  
Elevated Serum ◽  
Kidney Injury ◽  
Mice Model ◽  
Stat3 Signaling

Abstract Background Hypovolemic shock and septic challenge are two major causes of acute kidney injury (AKI) in the clinic course. Src homology 2 domain-containing phosphatase 2 (SHP2) is one of the major phosphatase protein tyrosine phosphatase (PTPs), which play a significant role in maintaining immunological homeostasis by regulating many facets of immune cell signaling. In this study, we explored whether SHP2 signaling contributed to AKI induced by hemorrhage (Hem) followed by cecal ligation and puncture (CLP) (Hem/CLP) and, further, if inactivation of SHP2 with the selective inhibitor, Phenylhydrazonopyrazolone sulfonate 1 (PHPS1), attenuated this injury. Methods Male C57BL/6 mice were subjected to Hem (a “priming” insult) followed by CLP or sham-Hem plus sham-CLP (S/S) as controls. Samples of blood and kidney were harvested at 24 h post CLP. The expression of neutrophil gelatinase-associated lipocalin (NGAL), high mobility group box 1 (HMGB1), caspase3 as well as SHP2:phospho-SHP2, extracellular-regulated kinase (Erk1/2):phospho-Erk1/2, and signal transducer and activator of transcription 3 (STAT3):phospho-STAT3 protein in kidney tissues were detected by Western blotting. The levels of creatinine (Cre) and blood urea nitrogen (BUN) in serum were measured according to the manufacturer’s instructions. Blood inflammatory cytokine/chemokine levels were detected by ELISA. Results Here we report that indices of kidney injury, such as BUN, Cre, NGAL in renal tissue and histopathologic change, were pronounced after Hem/CLP in comparison with that observed in the S/S group mice. Furthermore, while Hem/CLP elevated serum levels of inflammatory cytokine/ chemokine, and induced increased levels of HMGB1, SHP2:phospho-SHP2, Erk1/2:phospho-Erk1/2, as well asSTAT3:phospho-STAT3 protein expression in the kidney; treatment with PHPS1 markedly attenuated these Hem/CLP induced changes. Conclusions In conclusion, our data indicate that SHP2 inhibition attenuates AKI induced by our double-hit/sequential insult model of Hem/CLP and that this protective action may be attributable to its anti-inflammatory property in mitigating activation of the Erk1/2 and STAT3 signaling pathway. This finding we believe has important potential clinical implications and, thus, warrants further investigation.

scholarly journals Jagged1-mediated myeloid Notch1 signaling activates HSF1/Snail and controls NLRP3 inflammasome activation in liver inflammatory injury

2019 ◽  
Vol 17 (12) ◽  
pp. 1245-1256 ◽  
Author(s):  
Yuting Jin ◽  
Changyong Li ◽  
Dongwei Xu ◽  
Jianjun Zhu ◽  
Song Wei ◽  
...  
Keyword(s):  
Liver Injury ◽  
Inflammatory Response ◽  
Immune Cell ◽  
Ischemia Reperfusion ◽  
Inflammasome Activation ◽  
Inflammatory Injury ◽  
Notch1 Signaling ◽  
Caspase 1 ◽  
Hepatocellular Damage ◽  
Hepatocellular Apoptosis

AbstractNotch signaling plays important roles in the regulation of immune cell functioning during the inflammatory response. Activation of the innate immune signaling receptor NLRP3 promotes inflammation in injured tissue. However, it remains unknown whether Jagged1 (JAG1)-mediated myeloid Notch1 signaling regulates NLRP3 function in acute liver injury. Here, we report that myeloid Notch1 signaling regulates the NLRP3-driven inflammatory response in ischemia/reperfusion (IR)-induced liver injury. In a mouse model of liver IR injury, Notch1-proficient (Notch1FL/FL) mice receiving recombinant JAG1 showed a reduction in IR-induced liver injury and increased Notch intracellular domain (NICD) and heat shock transcription factor 1 (HSF1) expression, whereas myeloid-specific Notch1 knockout (Notch1M-KO) aggravated hepatocellular damage even with concomitant JAG1 treatment. Compared to JAG1-treated Notch1FL/FL controls, Notch1M-KO mice showed diminished HSF1 and Snail activity but augmented NLRP3/caspase-1 activity in ischemic liver. The disruption of HSF1 reduced Snail activation and enhanced NLRP3 activation, while the adoptive transfer of HSF1-expressing macrophages to Notch1M-KO mice augmented Snail activation and mitigated IR-triggered liver inflammation. Moreover, the knockdown of Snail in JAG1-treated Notch1FL/FL livers worsened hepatocellular functioning, reduced TRX1 expression and increased TXNIP/NLRP3 expression. Ablation of myeloid Notch1 or Snail increased ASK1 activation and hepatocellular apoptosis, whereas the activation of Snail increased TRX1 expression and reduced TXNIP, NLRP3/caspase-1, and ROS production. Our findings demonstrated that JAG1-mediated myeloid Notch1 signaling promotes HSF1 and Snail activation, which in turn inhibits NLRP3 function and hepatocellular apoptosis leading to the alleviation of IR-induced liver injury. Hence, the Notch1/HSF1/Snail signaling axis represents a novel regulator of and a potential therapeutic target for liver inflammatory injury.

scholarly journals SARS-CoV-2 vs. Hepatitis Virus Infection Risk in the Hemodialysis Population: What Should We Expect?

2021 ◽  
Vol 18 (11) ◽  
pp. 5748
Author(s):  
Luis D’Marco ◽  
María Jesús Puchades ◽  
Miguel Ángel Serra ◽  
Lorena Gandía ◽  
Sergio Romero-Alcaide ◽  
...  
Keyword(s):  
Hepatitis Virus ◽  
Contact Precaution ◽  
Hepatitis Viruses ◽  
International Consensus ◽  
Infection Treatment ◽  
High Incidence ◽  
Dramatic Rise ◽  
Infection Disease ◽  
Coronavirus Infection ◽  
Hepatitis Virus Infection

Since the dramatic rise of the coronavirus infection disease 2019 (COVID-19) pandemic, patients receiving dialysis have emerged as especially susceptible to this infection because of their impaired immunologic state, chronic inflammation and the high incidence of comorbidities. Although several strategies have thus been implemented to minimize the risk of transmission and acquisition in this population worldwide, the reported severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) seroprevalence varies across studies but is higher than in the general population. On the contrary, the screening for hepatitis viruses (HBV and HCV) has seen significant improvements in recent years, with vaccination in the case of HBV and effective viral infection treatment for HCV. In this sense, a universal SARS-CoV-2 screening and contact precaution appear to be effective in preventing further transmission. Finally, regarding the progress, an international consensus with updated protocols that prioritize between old and new indicators would seem a reasonable tool to address these unexpended changes for the nephrology community.

scholarly journals Spinal Cord Injury Increases Pro-inflammatory Cytokine Expression in Kidney at Acute and Sub-chronic Stages

Inflammation ◽  
2021 ◽  
Author(s):  
Shangrila Parvin ◽  
Clintoria R. Williams ◽  
Simone A. Jarrett ◽  
Sandra M. Garraway
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Inflammatory Response ◽  
Inflammatory Cytokine ◽  
Cardiovascular Health ◽  
Mrna Levels ◽  
Post Injury ◽  
Cord Injury ◽  
And Function ◽  
The Impact

Abstract— Accumulating evidence supports that spinal cord injury (SCI) produces robust inflammatory plasticity. We previously showed that the pro-inflammatory cytokine tumor necrosis factor (TNF)α is increased in the spinal cord after SCI. SCI also induces a systemic inflammatory response that can impact peripheral organ functions. The kidney plays an important role in maintaining cardiovascular health. However, SCI-induced inflammatory response in the kidney and the subsequent effect on renal function have not been well characterized. This study investigated the impact of high and low thoracic (T) SCI on C-fos, TNFα, interleukin (IL)-1β, and IL-6 expression in the kidney at acute and sub-chronic timepoints. Adult C57BL/6 mice received a moderate contusion SCI or sham procedures at T4 or T10. Uninjured mice served as naïve controls. mRNA levels of the proinflammatory cytokines IL-1β, IL-6, TNFα, and C-fos, and TNFα and C-fos protein expression were assessed in the kidney and spinal cord 1 day and 14 days post-injury. The mRNA levels of all targets were robustly increased in the kidney and spinal cord, 1 day after both injuries. Whereas IL-6 and TNFα remained elevated in the spinal cord at 14 days after SCI, C-fos, IL-6, and TNFα levels were sustained in the kidney only after T10 SCI. TNFα protein was significantly upregulated in the kidney 1 day after both T4 and T10 SCI. Overall, these results clearly demonstrate that SCI induces robust systemic inflammation that extends to the kidney. Hence, the presence of renal inflammation can substantially impact renal pathophysiology and function after SCI.

scholarly journals POS1225 INFLUENCE OF COLCHICINE PRESCRIPTION IN COVID19-RELATED HOSPITAL ADMISSIONS: A SURVIVAL ANALYSIS

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 896.2-896
Author(s):  
M. P. Álvarez ◽  
A. Madrid García ◽  
I. Perez-Sancristobal ◽  
J. I. Colomer ◽  
L. León ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Rheumatic Diseases ◽  
Hospital Admissions ◽  
Musculoskeletal Diseases ◽  
Tertiary Care ◽  
Secondary Outcome ◽  
P Value ◽  
Inflammatory Rheumatic Diseases ◽  
Cytokine Storm ◽  
Observation Period

Background:Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), triggers the innate immune system, leading in severe cases, an excessive immune response, which can lead to high levels of pro-inflammatory cytokines promoting a “cytokine storm”.To modulate this exaggerated inflammatory response, several clinical trials with already approved and well-known therapeutic agents that inhibit the inflammatory response, are being carried out. However, none of these drugs seems to achieve the desired results when treating COVID19.Colchicine, a drug often used in the management of patients with Rheumatic and Musculoskeletal diseases (RMDs), is one of the several drugs that are being currently tested for efficacy in COVID19 due to its anti-inflammatory effects.Objectives:To analyze association between colchicine prescription and COVID19-related hospital admissions in patients with Rheumatic and Musculoskeletal diseases (RMDs).Methods:Patients attending a rheumatology outpatient clinic from a tertiary care center in Madrid, Spain, from 1st September 2019 to 29th February 2020 were included.Patients were assigned as exposed or unexposed based on whether they were prescribed with colchicine in their last visit to the clinic during the 6 months before the start of the observation period. Treatment changes during the observation period were also considered. The primary outcome was COVID19-related hospital admissions occurring between March 1st and May 20th, 2020. Secondary outcome included COVID19-related mortality. Several weighting techniques for data balancing, based and non-based on the propensity score, followed by Cox regressions were performed to estimate the association of colchicine prescription on both outcomes.Results:9,379 patients entered in the study, with 406 and 9,002 exposed and unexposed follow-up periods, respectively. Generalized Boosted Models (GBM) and Empirical Balancing Calibration Weighting (EBCW) methods showed the best balance for COVID19-related hospital admissions. Colchicine prescription did not show a statistically significant association after covariable balancing (p-value = 0.195 and 0.059 for GBM and EBCW, respectively). Regarding mortality, the low number of events prevented a success variable balancing and analysis.Conclusion:Colchicine prescription does not play a significant protective or risk role in RMD patients regarding COVID19-related hospital admissions. Our observations could support the maintenance of colchicine prescription in those patients already being treated, as it is not associated with a worse prognosis.References:[1]Fernandez-Gutierrez B. COVID-19 with Pulmonary Involvement. An Autoimmune Disease of Known Cause. Reumatol Clin 2020; 16: 253–254.[2]Coperchini F, Chiovato L, Croce L, et al. The cytokine storm in COVID-19: An overview of the involvement of the chemokine/chemokine-receptor system. Cytokine Growth Factor Rev 2020; 53: 25–32.[3]Shaffer L. 15 drugs being tested to treat COVID-19 and how they would work. Nat Med. Epub ahead of print 15 May 2020. DOI: 10.1038/d41591-020-00019-9.[4]Fernandez-Gutierrez B, Leon L, Madrid A, et al. Hospital admissions in inflammatory rheumatic diseases during the COVID-19 pandemic: incidence and role of disease modifying agents. medRxiv 2020; 2020.05.21.20108696.[5]Freites Nuñez DD, Leon L, Mucientes A, et al. Risk factors for hospital admissions related to COVID-19 in patients with autoimmune inflammatory rheumatic diseases. Ann Rheum Dis 2020; 1–7.Disclosure of Interests:None declared

Sign in / Sign up

Export Citation Format

Share Document