scholarly journals DSS-induced inflammation in the colon drives a pro-inflammatory signature in the brain that is ameliorated by prophylactic treatment with the S100A9 inhibitor paquinimod

2021 ◽  
Author(s):  
Sarah Talley ◽  
Rasa Valiauga ◽  
Lillian Anderson ◽  
Abigail R Cannon ◽  
Mashkoor A Choudhry ◽  
...  
Keyword(s):  
Rna Sequencing ◽  
Inflammatory Cytokines ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Light Sheet ◽  
Positive Control ◽  
Light Sheet Microscopy ◽  
Cytokines And Chemokines ◽  
Organ Systems ◽  
The Brain

Background: Inflammatory Bowel Disease (IBD) is established to drive pathological sequelae in organ systems outside the intestine, including the central nervous system (CNS). Many patients exhibit cognitive deficits, particularly during disease flare. The connection between colonic inflammation and neuroinflammation remains unclear and characterization of the neuroinflammatory phenotype in the brain during colitis is ill-defined. Methods: Transgenic mice expressing a bioluminescent reporter of active caspase-1 were treated with 2% Dextran Sodium Sulfate (DSS) for 7 days to induce acute colitis, and colonic, systemic and neuroinflammation were assessed. In some experiments, mice were prophylactically treated with paquinimod (ABR-215757) to inhibit S100A9 inflammatory signaling. As a positive control for peripheral-induced neuroinflammation, mice were injected with lipopolysaccharide (LPS). Colonic, systemic and brain inflammatory cytokines and chemokines were measured by cytokine bead array (CBA) and Proteome profiler mouse cytokine array. Bioluminescence was quantified in the brain and caspase activation was confirmed by immunoblot. Immune cell infiltration into the CNS was measured by flow cytometry, while light sheet microscopy was used to monitor changes in resident microglia localization in intact brains during DSS or LPS-induced neuroinflammation. RNA sequencing was performed to identify transcriptomic changes occurring in the CNS of DSS-treated mice. Expression of inflammatory biomarkers were quantified in the brain and serum by qRT-PCR, ELISA and WB. Results: DSS-treated mice exhibited clinical hallmarks of colitis, including weight loss, colonic shortening and inflammation in the colon. We also detected a significant increase in inflammatory cytokines in the serum and brain, as well as caspase and microglia activation in the brain of mice with ongoing colitis. RNA sequencing of brains isolated from DSS-treated mice revealed differential expression of genes involved in the regulation of inflammatory responses. This inflammatory phenotype was similar to the signature detected in LPS-treated mice, albeit less robust and transient, as inflammatory gene expression returned to baseline following cessation of DSS. Pharmacological inhibition of S100A9, one of the transcripts identified by RNA sequencing, attenuated colitis severity and systemic and neuroinflammation. Conclusions: Our findings suggest that local inflammation in the colon drives systemic inflammation and neuroinflammation, and this can be ameliorated by inhibition of the S100 alarmin, S100A9.

scholarly journals DSS-induced inflammation in the colon drives a proinflammatory signature in the brain that is ameliorated by prophylactic treatment with the S100A9 inhibitor paquinimod

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Sarah Talley ◽  
Rasa Valiauga ◽  
Lillian Anderson ◽  
Abigail R. Cannon ◽  
Mashkoor A. Choudhry ◽  
...  
Keyword(s):  
Rna Sequencing ◽  
Inflammatory Cytokines ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Light Sheet ◽  
Positive Control ◽  
Light Sheet Microscopy ◽  
Cytokines And Chemokines ◽  
Organ Systems ◽  
The Brain

Abstract Background Inflammatory bowel disease (IBD) is established to drive pathological sequelae in organ systems outside the intestine, including the central nervous system (CNS). Many patients exhibit cognitive deficits, particularly during disease flare. The connection between colonic inflammation and neuroinflammation remains unclear and characterization of the neuroinflammatory phenotype in the brain during colitis is ill-defined. Methods Transgenic mice expressing a bioluminescent reporter of active caspase-1 were treated with 2% dextran sodium sulfate (DSS) for 7 days to induce acute colitis, and colonic, systemic and neuroinflammation were assessed. In some experiments, mice were prophylactically treated with paquinimod (ABR-215757) to inhibit S100A9 inflammatory signaling. As a positive control for peripheral-induced neuroinflammation, mice were injected with lipopolysaccharide (LPS). Colonic, systemic and brain inflammatory cytokines and chemokines were measured by cytokine bead array (CBA) and Proteome profiler mouse cytokine array. Bioluminescence was quantified in the brain and caspase activation was confirmed by immunoblot. Immune cell infiltration into the CNS was measured by flow cytometry, while light sheet microscopy was used to monitor changes in resident microglia localization in intact brains during DSS or LPS-induced neuroinflammation. RNA sequencing was performed to identify transcriptomic changes occurring in the CNS of DSS-treated mice. Expression of inflammatory biomarkers were quantified in the brain and serum by qRT-PCR, ELISA and WB. Results DSS-treated mice exhibited clinical hallmarks of colitis, including weight loss, colonic shortening and inflammation in the colon. We also detected a significant increase in inflammatory cytokines in the serum and brain, as well as caspase and microglia activation in the brain of mice with ongoing colitis. RNA sequencing of brains isolated from DSS-treated mice revealed differential expression of genes involved in the regulation of inflammatory responses. This inflammatory phenotype was similar to the signature detected in LPS-treated mice, albeit less robust and transient, as inflammatory gene expression returned to baseline following cessation of DSS. Pharmacological inhibition of S100A9, one of the transcripts identified by RNA sequencing, attenuated colitis severity and systemic and neuroinflammation. Conclusions Our findings suggest that local inflammation in the colon drives systemic inflammation and neuroinflammation, and this can be ameliorated by inhibition of the S100 alarmin, S100A9.

scholarly journals Imaging the dynamic recruitment of monocytes to the blood–brain barrier and specific brain regions during Toxoplasma gondii infection

2019 ◽  
Vol 116 (49) ◽  
pp. 24796-24807 ◽  
Author(s):  
Christine A. Schneider ◽  
Dario X. Figueroa Velez ◽  
Ricardo Azevedo ◽  
Evelyn M. Hoover ◽  
Cuong J. Tran ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
Blood Brain Barrier ◽  
Light Sheet ◽  
Brain Regions ◽  
Brain Barrier ◽  
Cell Segmentation ◽  
Cns Infection ◽  
Light Sheet Microscopy ◽  
Blood Brain ◽  
The Brain

Brain infection by the parasite Toxoplasma gondii in mice is thought to generate vulnerability to predation by mechanisms that remain elusive. Monocytes play a key role in host defense and inflammation and are critical for controlling T. gondii. However, the dynamic and regional relationship between brain-infiltrating monocytes and parasites is unknown. We report the mobilization of inflammatory (CCR2+Ly6Chi) and patrolling (CX3CR1+Ly6Clo) monocytes into the blood and brain during T. gondii infection of C57BL/6J and CCR2RFP/+CX3CR1GFP/+ mice. Longitudinal analysis of mice using 2-photon intravital imaging of the brain through cranial windows revealed that CCR2-RFP monocytes were recruited to the blood–brain barrier (BBB) within 2 wk of T. gondii infection, exhibited distinct rolling and crawling behavior, and accumulated within the vessel lumen before entering the parenchyma. Optical clearing of intact T. gondii-infected brains using iDISCO+ and light-sheet microscopy enabled global 3D detection of monocytes. Clusters of T. gondii and individual monocytes across the brain were identified using an automated cell segmentation pipeline, and monocytes were found to be significantly correlated with sites of T. gondii clusters. Computational alignment of brains to the Allen annotated reference atlas [E. S. Lein et al., Nature 445:168–176 (2007)] indicated a consistent pattern of monocyte infiltration during T. gondii infection to the olfactory tubercle, in contrast to LPS treatment of mice, which resulted in a diffuse distribution of monocytes across multiple brain regions. These data provide insights into the dynamics of monocyte recruitment to the BBB and the highly regionalized localization of monocytes in the brain during T. gondii CNS infection.

scholarly journals NF-κB Pathway as a Potential Target for Treatment of Critical Stage COVID-19 Patients

2020 ◽  
Vol 11 ◽  
Author(s):  
Ralf Kircheis ◽  
Emanuel Haasbach ◽  
Daniel Lueftenegger ◽  
Willm T. Heyken ◽  
Matthias Ocker ◽  
...  
Keyword(s):  
Immune Cell ◽  
Inflammatory Responses ◽  
Therapeutic Potential ◽  
Synergistic Effects ◽  
Wide Spectrum ◽  
Clinical Manifestations ◽  
Published Data ◽  
Critical Stage ◽  
Cytokines And Chemokines ◽  
Simultaneous Inhibition

Patients infected with SARS-CoV-2 show a wide spectrum of clinical manifestations ranging from mild febrile illness and cough up to acute respiratory distress syndrome, multiple organ failure, and death. Data from patients with severe clinical manifestations compared to patients with mild symptoms indicate that highly dysregulated exuberant inflammatory responses correlate with severity of disease and lethality. Epithelial-immune cell interactions and elevated cytokine and chemokine levels, i.e. cytokine storm, seem to play a central role in severity and lethality in COVID-19. The present perspective places a central cellular pro-inflammatory signal pathway, NF-κB, in the context of recently published data for COVID-19 and provides a hypothesis for a therapeutic approach aiming at the simultaneous inhibition of whole cascades of pro-inflammatory cytokines and chemokines. The simultaneous inhibition of multiple cytokines/chemokines is expected to have much higher therapeutic potential as compared to single target approaches to prevent cascade (i.e. redundant, triggering, amplifying, and synergistic) effects of multiple induced cytokines and chemokines in critical stage COVID-19 patients.

scholarly journals Comparison of Transparency and Shrinkage During Clearing of Insect Brains Using Media With Tunable Refractive Index

2020 ◽  
Vol 14 ◽  
Author(s):  
Bo M. B. Bekkouche ◽  
Helena K. M. Fritz ◽  
Elisa Rigosi ◽  
David C. O'Carroll
Keyword(s):  
Refractive Index ◽  
Rapid Development ◽  
Vacuum Treatment ◽  
Building Blocks ◽  
Light Sheet ◽  
Tracheal System ◽  
Light Sheet Microscopy ◽  
Tissue Shrinkage ◽  
Tunable Refractive Index ◽  
The Brain

Improvement of imaging quality has the potential to visualize previously unseen building blocks of the brain and is therefore one of the great challenges in neuroscience. Rapid development of new tissue clearing techniques in recent years have attempted to solve imaging compromises in thick brain samples, particularly for high resolution optical microscopy, where the clearing medium needs to match the high refractive index of the objective immersion medium. These problems are exacerbated in insect tissue, where numerous (initially air-filled) tracheal tubes branching throughout the brain increase the scattering of light. To date, surprisingly few studies have systematically quantified the benefits of such clearing methods using objective transparency and tissue shrinkage measurements. In this study we compare a traditional and widely used insect clearing medium, methyl salicylate combined with permanent mounting in Permount (“MS/P”) with several more recently applied clearing media that offer tunable refractive index (n): 2,2′-thiodiethanol (TDE), “SeeDB2” (in variants SeeDB2S and SeeDB2G matched to oil and glycerol immersion, n = 1.52 and 1.47, respectively) and Rapiclear (also with n = 1.52 and 1.47). We measured transparency and tissue shrinkage by comparing freshly dissected brains with cleared brains from dipteran flies, with or without addition of vacuum or ethanol pre-treatments (dehydration and rehydration) to evacuate air from the tracheal system. The results show that ethanol pre-treatment is very effective for improving transparency, regardless of the subsequent clearing medium, while vacuum treatment offers little measurable benefit. Ethanol pre-treated SeeDB2G and Rapiclear brains show much less shrinkage than using the traditional MS/P method. Furthermore, at lower refractive index, closer to that of glycerol immersion, these recently developed media offer outstanding transparency compared to TDE and MS/P. Rapiclear protocols were less laborious compared to SeeDB2, but both offer sufficient transparency and refractive index tunability to permit super-resolution imaging of local volumes in whole mount brains from large insects, and even light-sheet microscopy. Although long-term permanency of Rapiclear stored samples remains to be established, our samples still showed good preservation of fluorescence after storage for more than a year at room temperature.

scholarly journals Viral Infection of the Central Nervous System and Neuroinflammation Precede Blood-Brain Barrier Disruption during Japanese Encephalitis Virus Infection

2015 ◽  
Vol 89 (10) ◽  
pp. 5602-5614 ◽  
Author(s):  
Fang Li ◽  
Yueyun Wang ◽  
Lan Yu ◽  
Shengbo Cao ◽  
Ke Wang ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Japanese Encephalitis Virus ◽  
Inflammatory Cytokines ◽  
Japanese Encephalitis ◽  
Cytokines And Chemokines ◽  
The Central Nervous System ◽  
Ifn Γ ◽  
Bbb Permeability ◽  
The Brain

ABSTRACTJapanese encephalitis is an acute zoonotic, mosquito-borne disease caused by Japanese encephalitis virus (JEV). Japanese encephalitis is characterized by extensive inflammation in the central nervous system (CNS) and disruption of the blood-brain barrier (BBB). However, the pathogenic mechanisms contributing to the BBB disruption are not known. Here, using a mouse model of intravenous JEV infection, we show that virus titers increased exponentially in the brain from 2 to 5 days postinfection. This was accompanied by an early, dramatic increase in the level of inflammatory cytokines and chemokines in the brain. Enhancement of BBB permeability, however, was not observed until day 4, suggesting that viral entry and the onset of inflammation in the CNS occurred prior to BBB damage.In vitrostudies revealed that direct infection with JEV could not induce changes in the permeability of brain microvascular endothelial cell monolayers. However, brain extracts derived from symptomatic JEV-infected mice, but not from mock-infected mice, induced significant permeability of the endothelial monolayer. Consistent with a role for inflammatory mediators in BBB disruption, the administration of gamma interferon-neutralizing antibody ameliorated the enhancement of BBB permeability in JEV-infected mice. Taken together, our data suggest that JEV enters the CNS, propagates in neurons, and induces the production of inflammatory cytokines and chemokines, which result in the disruption of the BBB.IMPORTANCEJapanese encephalitis (JE) is the leading cause of viral encephalitis in Asia, resulting in 70,000 cases each year, in which approximately 20 to 30% of cases are fatal, and a high proportion of patients survive with serious neurological and psychiatric sequelae. Pathologically, JEV infection causes an acute encephalopathy accompanied by BBB dysfunction; however, the mechanism is not clear. Thus, understanding the mechanisms of BBB disruption in JEV infection is important. Our data demonstrate that JEV gains entry into the CNS prior to BBB disruption. Furthermore, it is not JEV infectionper se, but the inflammatory cytokines/chemokines induced by JEV infection that inhibit the expression of TJ proteins and ultimately result in the enhancement of BBB permeability. Neutralization of gamma interferon (IFN-γ) ameliorated the enhancement of BBB permeability in JEV-infected mice, suggesting that IFN-γ could be a potential therapeutic target. This study would lead to identification of potential therapeutic avenues for the treatment of JEV infection.

scholarly journals Neuroinvasion of SARS-CoV-2 in human and mouse brain

2021 ◽  
Vol 218 (3) ◽  
Author(s):  
Eric Song ◽  
Ce Zhang ◽  
Benjamin Israelow ◽  
Alice Lu-Culligan ◽  
Alba Vieites Prado ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Immune Cell ◽  
Multiple Organ ◽  
Type I ◽  
Organ Systems ◽  
The Central Nervous System ◽  
Interferon Responses ◽  
The Brain ◽  
Immune Cell Infiltrates

Although COVID-19 is considered to be primarily a respiratory disease, SARS-CoV-2 affects multiple organ systems including the central nervous system (CNS). Yet, there is no consensus on the consequences of CNS infections. Here, we used three independent approaches to probe the capacity of SARS-CoV-2 to infect the brain. First, using human brain organoids, we observed clear evidence of infection with accompanying metabolic changes in infected and neighboring neurons. However, no evidence for type I interferon responses was detected. We demonstrate that neuronal infection can be prevented by blocking ACE2 with antibodies or by administering cerebrospinal fluid from a COVID-19 patient. Second, using mice overexpressing human ACE2, we demonstrate SARS-CoV-2 neuroinvasion in vivo. Finally, in autopsies from patients who died of COVID-19, we detect SARS-CoV-2 in cortical neurons and note pathological features associated with infection with minimal immune cell infiltrates. These results provide evidence for the neuroinvasive capacity of SARS-CoV-2 and an unexpected consequence of direct infection of neurons by SARS-CoV-2.

scholarly journals Gut–neuroimmune interactions: the unexpected role of the immune system in brain development

2019 ◽  
Vol 41 (1) ◽  
pp. 36-41 ◽  
Author(s):  
Simon Spichak ◽  
Timothy G. Dinan ◽  
John F. Cryan
Keyword(s):  
Immune System ◽  
Brain Development ◽  
Neuronal Development ◽  
Inflammatory Responses ◽  
Later Life ◽  
Innate Immune ◽  
Brain Health ◽  
Cytokines And Chemokines ◽  
The Brain

How does the immune system impact brain development? The exciting and somewhat unexpected relationship between the immune system and the brain has become one of the most fascinating topics in neuroscience. Even though the immune system was initially implicated in resolving viral and bacterial threats, it is now becoming more evident that it also plays a role in processes in the brain, both under healthy and pathological conditions. This novel role of the immune system in brain health has been implicated in various psychopathologies where neurodevelopment, stress and mood are central. In particular, its role in healthy brain development is becoming more evident, and understanding neuroimmune communication is becoming crucial in treating neurodevelopmental and mood disorders in later life. In the brain, glia function as part of the innate immune system and are programmed to respond to pathogens and physical injury. They also play an important role in neuronal development and pruning. These cells communicate with and respond to chemical signals, such as cytokines and chemokines, which can then initiate or downregulate inflammatory responses. Finally, the trillions of microbes residing in the gut can also stimulate cytokine and chemokine responses in the periphery and play an important role in both immunity and brain development.

scholarly journals 3D Reconstruction of the Clarified Rat Hindbrain Choroid Plexus

2021 ◽  
Vol 9 ◽  
Author(s):  
Paola Perin ◽  
Riccardo Rossetti ◽  
Carolina Ricci ◽  
Daniele Cossellu ◽  
Simone Lazzarini ◽  
...  
Keyword(s):  
Choroid Plexus ◽  
Spatial Organization ◽  
Light Sheet ◽  
Dorsal Cochlear Nucleus ◽  
Horizontal Segment ◽  
Venous Outflow ◽  
Light Sheet Microscopy ◽  
Contact Points ◽  
The Brain ◽  
4Th Ventricle

The choroid plexus (CP) acts as a regulated gate between blood and cerebrospinal fluid (CSF). Despite its simple histology (a monostratified cuboidal epithelium overlying a vascularized stroma), this organ has remarkably complex functions several of which involve local interaction with cells located around ventricle walls. Our knowledge of CP structural organization is mainly derived from resin casts, which capture the overall features but only allow reconstruction of the vascular pattern surface, unrelated to the overlying epithelium and only loosely related to ventricular location. Recently, CP single cell atlases are starting to emerge, providing insight on local heterogeneities and interactions. So far, however, few studies have described CP spatial organization at the mesoscale level, because of its fragile nature and deep location within the brain. Here, using an iDISCO-based clearing approach and light-sheet microscopy, we have reconstructed the normal rat hindbrain CP (hCP) macro- and microstructure, using markers for epithelium, arteries, microvasculature, and macrophages, and noted its association with 4th ventricle-related neurovascular structures. The hCP is organized in domains associated to a main vessel (fronds) which carry a variable number of villi; the latter are enclosed by epithelium and may be flat (leaf-like) or rolled up to variable extent. Arteries feeding the hCP emerge from the cerebellar surface, and branch into straight arterioles terminating as small capillary anastomotic networks, which run within a single villus and terminate attaching multiple times to a large tortuous capillary (LTC) which ends into a vein. Venous outflow mostly follows arterial pathways, except for the lateral horizontal segment (LHS) and the caudal sagittal segment. The structure of fronds and villi is related to the microvascular pattern at the hCP surface: when LTCs predominate, leaflike villi are more evident and bulge from the surface; different, corkscrew-like villi are observed in association to arterioles reaching close to the CP surface with spiraling capillaries surrounding them. Both leaf-like and corkscrew-like villi may reach the 4th ventricle floor, making contact points at their tip, where no gap is seen between CP epithelium and ependyma. Contacts usually involve several adjacent villi and may harbor epiplexus macrophages. At the junction between medial (MHS) and lateral (LHS) horizontal segment, arterial supply is connected to the temporal bone subarcuate fossa, and venous outflow drains to a ventral vein which exits through the cochlear nuclei at the Luschka foramen. These vascular connections stabilize the hCP overall structure within the 4th ventricle but make MHS-LHS joint particularly fragile and very easily damaged when removing the brain from the skull. Even in damaged samples, however, CP fronds (or isolated villi) often remain strongly attached to the dorsal cochlear nucleus (DCN) surface; in these fronds, contacts are still present and connecting “bridges” may be seen, suggesting the presence of real molecular contacts rather than mere appositions.

scholarly journals Modulation of monocyte responses by progressive multiple sclerosis therapy.

2021 ◽  
Author(s):  
◽  
Carl Beyers
Keyword(s):  
Multiple Sclerosis ◽  
Inflammatory Cytokines ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Neurodegenerative Disorder ◽  
Cell Activity ◽  
Cell Subset ◽  
Disease Heterogeneity ◽  
Receptor Affinity ◽  
Anti Inflammatory

<p>Multiple sclerosis (MS) is an immune-mediated neurodegenerative disorder that is distinguished by neuroinflammation and demyelination. MS is severely debilitating and remains the most common cause of disability arising from non-traumatic brain and CNS damage in adults. In its progressive phase there are no effective treatments, so new therapy options are an urgent research priority. Extensive work has been done on the role of the adaptive immune system in contributing to the disease pathology and on the effects of therapies targeting lymphocytes in relapsing-remitting MS. Fewer studies have examined innate immune cells in people with progressive MS. This thesis addresses that gap by profiling monocyte phenotype and function in response to new and repurposed drugs that may provide benefit in progressive MS. This was achieved by modelling the drugs’ effects in vitro using peripheral blood cells from people with progressive MS and healthy subjects.   Clozapine is an atypical antipsychotic with broad receptor affinity that is primarily used to treat refractory schizophrenia. In addition to is antipsychotic action through dopamine receptor (DR) D2, its broad neuro-immune receptor affinity is thought to dampen inflammatory responses in the CNS. This thesis highlights clozapine’s anti-inflammatory effect by demonstrating a reduction in the expression of pro-inflammatory cytokines that are associated with MS pathology in treated monocytes. Clozapine also induced a significant increase in the expression of D1. We observed that D1 expression changes happened alongside alterations to immune cell activity and that MS participant monocytes were much more susceptible to DR expression changes compared to healthy people. Together this data substantiates clozapine as a potential treatment for progressive disease.   MIS416 is a large, non-soluble microparticle suspension that induces nuclear factor kappa B (NFB) dependent cytokine induction. We show here that monocytes are key cytokine responder cells to MIS416 and explore the molecular mechanism by demonstrating its effects on transcription factor activity. Our data showing increased production of cytokines by MIS416 suggests a route of treatment efficacy through tolerisation mechanisms, and by reducing inflammation through upregulation of anti-inflammatory cytokines and negative feedback from pro-inflammatory cytokine release. Furthermore, we demonstrate how disease heterogeneity, phenotype, and genotype could significantly affect drug response outcomes in patients who received the drug as part of a phase 2 clinical trial.   Much of this work was done using new spectral cytometer technology. Its use allowed for the novel approach that enabled the subtraction of autofluorescent noise from out data, and we demonstrate its efficient functioning, ease of use, and utility in acquiring high dimensional datasets. The resulting large dataset allowed us the opportunity to interrogate it using bioinformatics tools, and we show their utility as adjunct tools to conventional methods of gating and statistical analysis. These analyses help demonstrate that monocytes are a heterogenous immune cell subset that is functionally distinct in people with progressive MS when compared to monocytes from healthy individuals.</p>

scholarly journals NF-kappaB pathway as a potential target for treatment of critical stage COVID-19 patients

2020 ◽  
Author(s):  
Ralf Kircheis ◽  
Emanuel Haasbach ◽  
Daniel Lueftenegger ◽  
Will T. Heyken ◽  
Matthias Ocker ◽  
...  
Keyword(s):  
Immune Cell ◽  
Inflammatory Responses ◽  
Therapeutic Potential ◽  
Wide Spectrum ◽  
Clinical Manifestations ◽  
Published Data ◽  
Critical Stage ◽  
Cytokines And Chemokines ◽  
Simultaneous Inhibition ◽  
Nf Kappab

Abstract Patients infected with SARS-CoV-2 show a wide spectrum of clinical manifestations ranging from mild febrile illness and cough up to acute respiratory distress syndrome, multiple organ failure and death. Data from patients with severe clinical manifestations compared to patients with mild symptoms indicate that highly dysregulated exuberant inflammatory responses correlate with severity of disease and lethality. Epithelial-immune cell interactions and elevated cytokine and chemokine levels, i.e. cytokine storm, seem to play a central role in severity and lethality in COVID-19. The present perspective places a central cellular pro-inflammatory signal pathway, NF-kappaB, in the context of recently published data for COVID-19 and provides a hypothesis for a therapeutic approach aiming at the simultaneous inhibition of whole cascades of pro-inflammatory cytokines and chemokines. The simultaneous inhibition of multiple cytokines/chemokines is expected to have much higher therapeutic potential as compared to single target approaches to prevent cascade (i.e. triggering, synergistic, and redundant) effects of multiple induced cytokines and chemokines in critical stage COVID-19 patients.

Sign in / Sign up

Export Citation Format

Share Document