Estrogen receptor α phosphorylated at Ser216 confers inflammatory function to mouse microglia

Abstract Background Estrogen has been suggested to regulate anti-inflammatory signaling in brain microglia through estrogen receptor α (ERα), the only resident immune cells of the brain. The mechanism of how ERα regulates is not well understood. Previously, ERα is phosphorylated at Ser216 in mouse neutrophils, regulating their infiltration into the uterus. Therefore, ERα has now been examined as to its phosphorylation in microglia to regulate their inflammatory functions.MethodsAn antibody against an anti-phospho-S216 peptide of ERα (αP-S216) was used for double immunofluorescence staining to detect to ERα in cultured microglia. A knock-in (KI) mouse line bearing the phosphorylation-blocked ERα mutation S216A (ERα KI) was generated to examine whether this phosphorylation regulate immune functions of microglia.ResultsPhosphorylated ERα at Ser216 was present in microglia but not astrocytes. Staining with an anti-Iba-1 antibody showed that microglia activation was augmented in substantial nigra of ERα KI brains. Lipopolysaccharide (LPS) treatments aggravated microglia activation in ERα KI brains, pro-inflammatory cytokines were increased while anti-inflammatory cytokines were decreased at mRNA and protein levels in whole brain extracts. These increases and decreases of cytokine proteins were also observed in LPS-treated microglia cultured from brains of ERα KI neonates. FACS analysis revealed that ERα KI mutation increased number of IL-6 producing microglia and apoptosis. ERα KI mice decreased motor connection ability in Rotarod tests.ConclusionsBlocking of Ser216 phosphorylation aggravated microglia activation and inflammation of mouse brain, thus confirming that phosphorylated ERα exerts anti-inflammatory functions. ERα KI mice enable us to further investigate the mechanism by which phosphorylated ERα regulates brain immunity and inflammation.

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Estrogen receptor α phosphorylated at Ser216 confers inflammatory function to mouse microglia

10.21203/rs.2.18935/v2 ◽

2020 ◽

Author(s):

Sawako Shindo ◽

Shih-Heng Chen ◽

Saki Gotoh ◽

Kosuke Yokobori ◽

Hao Hu ◽

...

Keyword(s):

Estrogen Receptor ◽

Inflammatory Cytokines ◽

Estrogen Receptor Α ◽

Brain Diseases ◽

Antibody Array ◽

Mouse Uterus ◽

Glia Cells ◽

Protein Levels ◽

Anti Inflammatory ◽

The Brain

Abstract Background Estrogen receptor α (ERα) has been suggested to regulate anti-inflammatory signaling in brain microglia, the only resident immune cells in the brain. ERα conserves the phosphorylation motif at Ser216 within the DNA binding domain. Previously, Ser216 was found to be phosphorylated in neutrophils infiltrating into the mouse uterus and to enable ERα to regulate migration. Given the implication of this phosphorylation in immune regulation, ERα was examined in mouse microglia to determine if Ser216 is phosphorylated and regulates microglia’s inflammation. It was found that Ser216 was constitutively phosphorylated in microglia and demonstrated that in the absence of phosphorylated ERα in ERα KI brains microglia inflamed, confirming that phosphorylation confers ERα with anti-inflammatory capability. ERα KI mice were obese and weakened motor ability. Methods Mixed glia cells were prepared from brains of 2-days-old neonates and cultured to mature and isolate microglia. An antibody against an anti-phospho-S216 peptide of ERα (αP-S216) was used to detect phosphorylated ERα in double immunofluorescence staining with ERα antibodies and a microglia maker Iba-1 antibody. A knock-in (KI) mouse line bearing the phosphorylation-blocked ERα S216A mutation (ERα KI) was generated to examine inflammation-regulating functions of phosphorylated ERα in microglia. RT-PCR, antibody array, ELISA and FACS assays were employed to measure expressions of pro- or anti-inflammatory cytokines at their mRNA and protein levels. Rotarod tests were performed to examine motor connection ability.Results Double immune staining of mixed glia cells showed that ERα is phosphorylated at Ser216 in microglia, but not astrocytes. Immunohistochemistry with an anti-Iba-1 antibody showed that microglia cells were swollen and shortened branches in the substantial nigra (SN) of ERα KI brains, indicating the spontaneous activation of microglia as observed with those of lipopolysaccharide (LPS)-treated ERα WT brains. Pro-inflammatory cytokines were up-regulated in the brain of ERα KI brains as well as cultured microglia, whereas anti-inflammatory cytokines were down-regulated. FACS analysis showed that the number of IL-6 producing and apoptotic microglia increased in those prepared from ERα KI brains. Times of ERα KI mice on rod were shortened in Rotarod tests. Conclusions Blocking of Ser216 phosphorylation aggravated microglia activation and inflammation of mouse brain, thus confirming that phosphorylated ERα exerts anti-inflammatory functions. ERα KI mice enable us to further investigate the mechanism by which phosphorylated ERα regulates brain immunity and inflammation and brain diseases.

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Cerebrospinal fluid biomarkers of neuroinflammation in children with hydrocephalus and shunt malfunction

Fluids and Barriers of the CNS ◽

10.1186/s12987-021-00237-4 ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Carolyn A. Harris ◽

Diego M. Morales ◽

Rooshan Arshad ◽

James P. McAllister ◽

David D. Limbrick

Keyword(s):

Cerebrospinal Fluid ◽

Inflammatory Cytokines ◽

Protein Concentration ◽

Shunt Revision ◽

Csf Shunt ◽

Shunt Failure ◽

Revision Operation ◽

Protein Levels ◽

Anti Inflammatory ◽

Pro Inflammatory Cytokines

Abstract Background Approximately 30% of cerebrospinal fluid (CSF) shunt systems for hydrocephalus fail within the first year and 98% of all patients will have shunt failure in their lifetime. Obstruction remains the most common reason for shunt failure. Previous evidence suggests elevated pro-inflammatory cytokines in CSF are associated with worsening clinical outcomes in neuroinflammatory diseases. The aim of this study was to determine whether cytokines and matrix metalloproteinases (MMPs) contribute towards shunt failure in hydrocephalus. Methods Using multiplex ELISA, this study examined shunt failure through the CSF protein concentration profiles of select pro-inflammatory and anti-inflammatory cytokines, as well as select MMPs. Interdependencies such as the past number of previous revisions, length of time implanted, patient age, and obstruction or non-obstruction revision were examined. The pro-inflammatory cytokines were IL-1β, IL-2, IL-5, IL-6, IL-8, IL-12, IL-17, TNF-α, GM-CSF, IFN-γ. The anti-inflammatory cytokines were IL-4 and IL-10, and the MMPs were MMP-2, MMP-3, MMP-7, MMP-9. Protein concentration is reported as pg/mL for each analyte. Results Patient CSF was obtained at the time of shunt revision operation; all pediatric (< 18), totaling n = 38. IL-10, IL-6, IL-8 and MMP-7 demonstrated significantly increased concentrations in patient CSF for the non-obstructed subgroup. Etiological examination revealed IL-6 was increased in both obstructed and non-obstructed cases for PHH and congenital hydrocephalic patients, while IL-8 was higher only in PHH patients. In terms of number of past revisions, IL-10, IL-6, IL-8, MMP-7 and MMP-9 progressively increased from zero to two past revisions and then remained low for subsequent revisions. This presentation was notably absent in the obstruction subgroup. Shunts implanted for three months or less showed significantly increased concentrations of IL-6, IL-8, and MMP-7 in the obstruction subgroup. Lastly, only patients aged six months or less presented with significantly increased concentration of IL-8 and MMP-7. Conclusion Non-obstructive cases are reported here to accompany significantly higher CSF cytokine and MMP protein levels compared to obstructive cases for IL-10, IL-6, IL-8, MMP-7 and MMP-9. A closer examination of the definition of obstruction and the role neuroinflammation plays in creating shunt obstruction in hydrocephalic patients is suggested.

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Pro-inflammatory cytokines reduce human TAFI expression via tristetraprolin-mediated mRNA destabilisation and decreased binding of HuR

Thrombosis and Haemostasis ◽

10.1160/th14-08-0653 ◽

2015 ◽

Vol 114 (08) ◽

pp. 337-349 ◽

Cited By ~ 7

Author(s):

Dragana Komnenov ◽

Corey Scipione ◽

Zainab Bazzi ◽

Justin Garabon ◽

Marlys Koschinsky ◽

...

Keyword(s):

Inflammatory Cytokines ◽

Inflammatory Mediators ◽

Hepg2 Cells ◽

Inflammatory Cells ◽

Gene Encoding ◽

Protein Levels ◽

Anti Inflammatory ◽

Mechanistic Basis ◽

Pro Inflammatory Cytokines

SummaryThrombin activatable fibrinolysis inhibitor (TAFI) is the zymogen form of a basic carboxypeptidase (TAFIa) with both anti-fibrinolytic and anti-inflammatory properties. The role of TAFI in inflammatory disease is multifaceted and involves modulation both of specific inflammatory mediators as well as of the behaviour of inflammatory cells. Moreover, as suggested by in vitro studies, inflammatory mediators are capable of regulating the expression of CPB2, the gene encoding TAFI. In this study we addressed the hypothesis that decreased TAFI levels observed in inflammation are due to post-transcriptional mechanisms. Treatment of human HepG2 cells with pro-inflammatory cytokines TNFα, IL-6 in combination with IL-1β, or with bacterial lipopolysaccharide (LPS) decreased TAFI protein levels by approximately two-fold over 24 to 48 hours of treatment. Conversely, treatment of HepG2 cells with the anti-inflammatory cytokine IL-10 increased TAFI protein levels by two-fold at both time points. We found that the mechanistic basis for this modulation of TAFI levels involves binding of tristetraprolin (TTP) to the CPB2 3′-UTR, which mediates CPB2 mRNA destabilisation. In this report we also identified that HuR, another ARE-binding protein but one that stabilises transcripts, is capable of binding the CBP2 3’UTR. We found that pro-inflammatory mediators reduce the occupancy of HuR on the CPB2 3’-UTR and that the mutation of the TTP binding site in this context abolishes this effect, although TTP and HuR appear to contact discrete binding sites. Interestingly, all of the mediators tested appear to increase TAFI protein expression in THP-1 macrophages, likewise through effects on CPB2 mRNA stability.

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Immunosuppressant Cyclosporin A-Based Regulation of Lipopolysaccharide-Triggered Pro- and Anti-Inflammatory Cytokines in the Genital Tract of Female Rabbits

10.20944/preprints201811.0289.v1 ◽

2018 ◽

Author(s):

Li-Qin Yang ◽

Qiu-Ying Wu ◽

Xuan-Yu Chen ◽

Chun Wang ◽

Zhang Yan ◽

...

Keyword(s):

Mrna Expression ◽

Inflammatory Cytokines ◽

Genital Tract ◽

Protein Production ◽

Control Group ◽

Protein Levels ◽

Lps Challenge ◽

Anti Inflammatory ◽

Uterine Body ◽

Pro Inflammatory Cytokines

In this study, we evaluated the effects of Cyclosporine A (CsA) on Lipopolysaccharide (LPS)-induced cytokine production in the genital tract of female rabbits. Twelve sexually mature and healthy female rabbits were randomly divided into four groups (n = 3 each). The rabbits in the LPS group were given an intrauterine infusion of Escherichia coli LPS (4 mg/kg body weight (BW)). Rabbits in the CsA group were given CsA (20 mg/kg BW). Rabbits in the LPS + CsA group were given LPS (4 mg/kg BW) and CsA (20 mg/kg BW). The control group received only LPS and CsA carrier. The gene expression and protein levels of pro- and anti-inflammatory cytokines were observed using qRT-PCR and immuno-histochemical (IHC) assay, respectively. Our study showed that IL-1β, IL-6, IL-8, TNF-α, IFN-γ, IL-4, IL-10, IL-13, and TGF-β were expressed in female genital organs. The LPS challenge increased the mRNA expression of IL-6 and TNF-α in the uterine body and IL-1β in the uterotubal junction compared to the control group. CsA increased the basal mRNA expression of anti-inflammatory cytokines (i.e., IL-4 in the uterine body, uterotubal junction, and oviductal ampulla; IL-10 in the cervix, oviductal isthmus, and ampulla; and TGF-β in the uterotubal junction and oviductal ampulla) and pro-inflammatory cytokines (i.e., IL-6 and IL-8 in the cervix; IL-1β in the oviductal isthmus; TNF-α in the oviductal ampulla; and IFN-γ in the uterine body compared to the control group). In addition, CsA inhibited the mRNA expression of pro-inflammatory cytokines, such as IL-6 in the uterine body, uterotubal junction, and oviductal isthmus; TNF-α in the uterine body; and IFN-γ in the uterotubal junction and oviductal isthmus induced by the LPS challenge. The IHC assay showed the LPS-induced increase in protein production of IL-6 in the uterine body and oviductal isthmus. CsA increased the protein production of IL-10 in the cervix, uterine body, oviductal ampulla, and isthmus. Moreover, CsA decreased the protein production of IL-6 in the uterine body and oviductal isthmus induced by LPS.

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Anti-inflammatory Activity of a Polypeptide Fraction From Achyranthes bidentate in Amyloid β Oligomers Induced Model of Alzheimer’s Disease

Frontiers in Pharmacology ◽

10.3389/fphar.2021.716177 ◽

2021 ◽

Vol 12 ◽

Author(s):

Xiangyu Ge ◽

Yitong Wang ◽

Shu Yu ◽

Xuemin Cao ◽

Yicong Chen ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Inflammatory Cytokines ◽

Mrna Levels ◽

Bv2 Microglia ◽

M1 Phenotype ◽

Anti Inflammatory ◽

The Brain ◽

M2 Phenotype ◽

Pro Inflammatory Cytokines

Neuroinflammation plays a crucial role in neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), and anti-inflammation has been considered as a potential therapeutic strategy. Achyranthes bidentate polypeptide fraction k (ABPPk) was shown to protect neurons from death and suppress microglia and astrocyte activation in PD model mice. However, how ABPPk regulates neuroinflammation to exert a neuroprotective role remains unclear. Toxic Aβ oligomers (AβOs) can trigger inflammatory response and play an important role in the pathogenesis of AD. In the present study, for the first time, we investigated the effects and underlying mechanisms of ABPPk on neuroinflammation in AβOs-induced models of AD. In vitro, ABPPk pretreatment dose-dependently inhibited AβOs-induced pro-inflammatory cytokines mRNA levels in BV2 and primary microglia. ABPPk pretreatment also reduced the neurotoxicity of BV2 microglia-conditioned media on primary hippocampal neurons. Furthermore, ABPPk down-regulated the AβOs-induced phosphorylation of IκBα and NF-κB p65 as well as the expression of NLRP3 in BV2 microglia. In vivo, ABPPk pre-administration significantly improved locomotor activity, alleviated memory deficits, and rescued neuronal degeneration and loss in the hippocampus of AβOs-injected mice. ABPPk inhibited the activation of microglia in hippocampal CA3 region and suppressed the activation of NF-κB as well as the expression of NLRP3, cleaved caspase-1, and ASC in the brain after AβOs injection. ABPPk hindered the release of pro-inflammatory cytokines and promoted the release of anti-inflammatory cytokines in the brain. Notably, the polarization experiment on BV2 microglia demonstrated that ABPPk inhibited M1-phenotype polarization and promoted M2-phenotype polarization by activating the LPS- or AβOs-impaired autophagy in microglia. Taken together, our observations indicate that ABPPk can restore the autophagy of microglia damaged by AβOs, thereby promoting M2-phenotype polarization and inhibiting M1-phenotype polarization, thus playing a role in regulating neuroinflammation and alleviating neurotoxicity.

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AAnti-Inflammatory Effects of Plasma Circulating Exosomes Obtained from Normal-Weight and Obese Subjects on Hepatocytes

Endocrine Metabolic & Immune Disorders - Drug Targets ◽

10.2174/1871530320666200505121426 ◽

2020 ◽

Vol 20 ◽

Author(s):

Reza Afrisham ◽

Sahar Sadegh-Nejadi ◽

Reza Meshkani ◽

Solaleh Emamgholipour ◽

Molood Bagherieh ◽

...

Keyword(s):

Inflammatory Cytokines ◽

Hepg2 Cells ◽

Human Liver ◽

Liver Cells ◽

Normal Weight ◽

Protein Levels ◽

Human Liver Cells ◽

Tnf Α ◽

Anti Inflammatory

Introduction: Obesity is a disorder with low-grade chronic inflammation that plays a key role in the hepatic inflammation and steatosis. Moreover, there are studies to support the role of exosomes in the cellular communications, the regulation of metabolic homeostasis and immunomodulatory activity. Accordingly, we aimed to evaluate the influence of plasma circulating exosomes derived from females with normal-weight and obesity on the secretion of inflammatory cytokines in human liver cells. Methods: Plasma circulating exosomes were isolated from four normal (N-Exo) and four obese (O-Exo) women. The exosomes were characterized and approved for CD63 expression (common exosomal protein marker) and morphology/size using the western blot and TEM methods, respectively. The exosomes were used for stimulation of HepG2 cells in vitro. After 24 h incubation, the protein levels of TNF-α,IL-6, and IL-1β were measured in the culture supernatant of HepG2 cells using the ELISA kit. Results: The protein levels of IL-6 and TNF-α in the cells treated with O-Exo and N-Exo reduced significantly in comparison with control group (P=0.039 and P<0.001 respectively), while significance differences were not found between normal and obese groups (P=0.808, and P=0.978 respectively). However, no significant differences were found between three groups in term of IL-1β levels (P=0.069). Based on the correlation analysis, the protein levels of IL-6 were positively correlated with TNF-α (r 0.978, P<0.001). Conclusion: These findings suggest that plasma circulating exosomes have probably anti-inflammatory properties independently from body mass index and may decrease the secretion of inflammatory cytokines in liver. However, further investigations in vitro and in vivo are needed to address the anti-inflammatory function of N-Exo and O-Exo in human liver cells and/or other cells.

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Computational Identification of Potential Anti-Inflammatory Natural Compounds Targeting the p38 Mitogen-Activated Protein Kinase (MAPK): Implications for COVID-19-Induced Cytokine Storm

Biomolecules ◽

10.3390/biom11050653 ◽

2021 ◽

Vol 11 (5) ◽

pp. 653

Author(s):

Seth O. Asiedu ◽

Samuel K. Kwofie ◽

Emmanuel Broni ◽

Michael D. Wilson

Keyword(s):

Molecular Docking ◽

P38 Mapk ◽

Inflammatory Cytokines ◽

Binding Energies ◽

Mitogen Activated Protein Kinase ◽

Inflammatory Activity ◽

Computational Techniques ◽

Cytokine Storm ◽

Anti Inflammatory ◽

Pro Inflammatory Cytokines

Severely ill coronavirus disease 2019 (COVID-19) patients show elevated concentrations of pro-inflammatory cytokines, a situation commonly known as a cytokine storm. The p38 MAPK receptor is considered a plausible therapeutic target because of its involvement in the platelet activation processes leading to inflammation. This study aimed to identify potential natural product-derived inhibitory molecules against the p38α MAPK receptor to mitigate the eliciting of pro-inflammatory cytokines using computational techniques. The 3D X-ray structure of the receptor with PDB ID 3ZS5 was energy minimized using GROMACS and used for molecular docking via AutoDock Vina. The molecular docking was validated with an acceptable area under the curve (AUC) of 0.704, which was computed from the receiver operating characteristic (ROC) curve. A compendium of 38,271 natural products originating from Africa and China together with eleven known p38 MAPK inhibitors were screened against the receptor. Four potential lead compounds ZINC1691180, ZINC5519433, ZINC4520996 and ZINC5733756 were identified. The compounds formed strong intermolecular bonds with critical residues Val38, Ala51, Lys53, Thr106, Leu108, Met109 and Phe169. Additionally, they exhibited appreciably low binding energies which were corroborated via molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) calculations. The compounds were also predicted to have plausible pharmacological profiles with insignificant toxicity. The molecules were also predicted to be anti-inflammatory, kinase inhibitors, antiviral, platelet aggregation inhibitors, and immunosuppressive, with probable activity (Pa) greater than probable inactivity (Pi). ZINC5733756 is structurally similar to estradiol with a Tanimoto coefficient value of 0.73, which exhibits anti-inflammatory activity by targeting the activation of Nrf2. Similarly, ZINC1691180 has been reported to elicit anti-inflammatory activity in vitro. The compounds may serve as scaffolds for the design of potential biotherapeutic molecules against the cytokine storm associated with COVID-19.

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PARP7 and Mono-ADP-Ribosylation Negatively Regulate Estrogen Receptor α Signaling in Human Breast Cancer Cells

Cells ◽

10.3390/cells10030623 ◽

2021 ◽

Vol 10 (3) ◽

pp. 623

Author(s):

Marit Rasmussen ◽

Susanna Tan ◽

Venkata S. Somisetty ◽

David Hutin ◽

Ninni Elise Olafsen ◽

...

Keyword(s):

Breast Cancer ◽

Estrogen Receptor ◽

Protein Modification ◽

Target Genes ◽

Estrogen Receptor Α ◽

Transactivation Domain ◽

Adp Ribosylation ◽

Protein Levels ◽

17Β Estradiol ◽

Mcf 7

ADP-ribosylation is a post-translational protein modification catalyzed by a family of proteins known as poly-ADP-ribose polymerases. PARP7 (TIPARP; ARTD14) is a mono-ADP-ribosyltransferase involved in several cellular processes, including responses to hypoxia, innate immunity and regulation of nuclear receptors. Since previous studies suggested that PARP7 was regulated by 17β-estradiol, we investigated whether PARP7 regulates estrogen receptor α signaling. We confirmed the 17β-estradiol-dependent increases of PARP7 mRNA and protein levels in MCF-7 cells, and observed recruitment of estrogen receptor α to the promoter of PARP7. Overexpression of PARP7 decreased ligand-dependent estrogen receptor α signaling, while treatment of PARP7 knockout MCF-7 cells with 17β-estradiol resulted in increased expression of and recruitment to estrogen receptor α target genes, in addition to increased proliferation. Co-immunoprecipitation assays revealed that PARP7 mono-ADP-ribosylated estrogen receptor α, and mass spectrometry mapped the modified peptides to the receptor’s ligand-independent transactivation domain. Co-immunoprecipitation with truncated estrogen receptor α variants identified that the hinge region of the receptor is required for PARP7-dependent mono-ADP-ribosylation. These results imply that PARP7-mediated mono-ADP-ribosylation may play an important role in estrogen receptor positive breast cancer.

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Expression of Estrogen Receptor α by Decidual Macrophages in Preeclampsia

Biomedicines ◽

10.3390/biomedicines9020191 ◽

2021 ◽

Vol 9 (2) ◽

pp. 191 ◽

Cited By ~ 1

Author(s):

Polina Vishnyakova ◽

Anastasiya Poltavets ◽

Maria Nikitina ◽

Konstantin Midiber ◽

Liudmila Mikhaleva ◽

...

Keyword(s):

Estrogen Receptor ◽

Late Onset ◽

Normal Pregnancy ◽

Estrogen Receptor Α ◽

Control Group ◽

Tissue Fluid ◽

Tissue Samples ◽

Cultural Methods ◽

Anti Inflammatory ◽

Early Onset Preeclampsia

Preeclampsia is a gestation-associated hypertensive syndrome that threatens the life and health of the mother and the child. The condition is presumably caused by systemic failure with a strong involvement of innate immunity. In particular, it has been associated with flexible phenotypes of macrophages, which depend on the molecules circulating in the blood and tissue fluid, such as cytokines and hormones. This study aimed at a comparative evaluation of pro-inflammatory (TNFα) and anti-inflammatory (CD206, MMP9, HGF) markers, as well as the levels of estrogen receptor α, expressed by decidual macrophages in normal pregnancy and in patients with early- and late-onset preeclampsia. The tissue samples of decidua basalis were examined by immunohistochemistry and Western blotting. Isolation of decidual macrophages and their characterization were performed using cultural methods, flow cytometry and real-time PCR. Over 50% of the isolated decidual macrophages were positive for the pan-macrophage marker CD68. In the early-onset preeclampsia group, the levels of estrogen receptor α in decidua were significantly decreased. Furthermore, significantly decreased levels of HGF and CD206 were observed in both preeclampsia groups compared with the control group. The observed downregulation of estrogen receptor α, HGF and CD206 may contribute to the balance of pro- and anti-inflammatory macrophages and thereby to pathogenesis of preeclampsia.

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Role of Inflammatory Cytokines in COVID-19 Patients: A Review on Molecular Mechanisms, Immune Functions, Immunopathology and Immunomodulatory Drugs to Counter Cytokine Storm

Vaccines ◽

10.3390/vaccines9050436 ◽

2021 ◽

Vol 9 (5) ◽

pp. 436

Author(s):

Ali A. Rabaan ◽

Shamsah H. Al-Ahmed ◽

Javed Muhammad ◽

Amjad Khan ◽

Anupam A Sule ◽

...

Keyword(s):

Inflammatory Cytokines ◽

Inflammatory Markers ◽

Therapeutic Drug ◽

Molecular Pathways ◽

Cytokine Storm ◽

Immunomodulatory Drugs ◽

Alveolar Cells ◽

Systemic Complications ◽

Anti Inflammatory ◽

Pro Inflammatory Cytokines

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a severe pandemic of the current century. The vicious tentacles of the disease have been disseminated worldwide with unknown complications and repercussions. Advanced COVID-19 syndrome is characterized by the uncontrolled and elevated release of pro-inflammatory cytokines and suppressed immunity, leading to the cytokine storm. The uncontrolled and dysregulated secretion of inflammatory and pro-inflammatory cytokines is positively associated with the severity of the viral infection and mortality rate. The secretion of various pro-inflammatory cytokines such as TNF-α, IL-1, and IL-6 leads to a hyperinflammatory response by recruiting macrophages, T and B cells in the lung alveolar cells. Moreover, it has been hypothesized that immune cells such as macrophages recruit inflammatory monocytes in the alveolar cells and allow the production of large amounts of cytokines in the alveoli, leading to a hyperinflammatory response in severely ill patients with COVID-19. This cascade of events may lead to multiple organ failure, acute respiratory distress, or pneumonia. Although the disease has a higher survival rate than other chronic diseases, the incidence of complications in the geriatric population are considerably high, with more systemic complications. This review sheds light on the pivotal roles played by various inflammatory markers in COVID-19-related complications. Different molecular pathways, such as the activation of JAK and JAK/STAT signaling are crucial in the progression of cytokine storm; hence, various mechanisms, immunological pathways, and functions of cytokines and other inflammatory markers have been discussed. A thorough understanding of cytokines’ molecular pathways and their activation procedures will add more insight into understanding immunopathology and designing appropriate drugs, therapies, and control measures to counter COVID-19. Recently, anti-inflammatory drugs and several antiviral drugs have been reported as effective therapeutic drug candidates to control hypercytokinemia or cytokine storm. Hence, the present review also discussed prospective anti-inflammatory and relevant immunomodulatory drugs currently in various trial phases and their possible implications.

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