An in vitro test system for compounds that modulate human inflammatory macrophage polarization

Shiratori, Hiromi; Feinweber, Carmen; Luckhardt, Sonja; Wallner, Nadja; Geißlinger, Gerd; Weigert, Andreas; Parnham, Michael J.

doi:10.1016/j.ejphar.2018.06.017

Cited by 29 publications

(21 citation statements)

References 51 publications

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“…In this study, we demonstrate that HCQ can mimic the effect of anti-IL-6 antibody by greatly redu-cing the levels of Il-6 in the critically ill COVID-19 patients. In addition, HCQ can modulate human inflammatory macrophage polarization via downregulating M1 but upregulating M2 macrophages (Shiratori et al, 2018;Sarzi-Puttini et al, 2020), and inhibit proinflammatory cytokines through inhibition of lysosomal-autophagy pathways (He et al, 2011) and formation of double membrane vesicles (He et al, 2011;Plantone and Koudriavtseva, 2018), a process required for genome replication by the SARS coronavirus replication complex (Snijder et al, 2006). Thus, the anti-inflammatory action of HCQ in combination with its inhibitory activity of viral replication may contribute greatly to its therapeutic effects on critically ill COVID-19 patients.…”

Section: Discussionmentioning

confidence: 99%

Low dose of hydroxychloroquine reduces fatality of critically ill patients with COVID-19

Chen

et al. 2020

Sci. China Life Sci.

148

161

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Section: Discussionmentioning

confidence: 99%

Low dose of hydroxychloroquine reduces fatality of critically ill patients with COVID-19

Chen

et al. 2020

Sci. China Life Sci.

148

161

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“…While studies are mixed on this topic, and the balance of M1 to M2 macrophage polarization may differ depending on the local microenvironment, hydroxychloroquine has been shown in at least one study to block the polarization of macrophages to an M1 inflammatory subtype, 41 and it is predicted to interfere with glycosylation of a number of proteins involved in the humoral immune response, possibly including the macrophage FcR gamma IgG receptor and other immunomodulatory proteins, potentially through inhibition of UDP‐ N ‐acetylglucosamine 2‐epimerase. In combination with potential other immunomodulatory effects, this could possibly blunt the progression of COVID‐19 pneumonia all to way up to ARDS where a potential over‐conversion to an inflammatory M1 macrophage subtype occurs in response to a postulated brisk humoral immune response to the SARS‐CoV‐2 spike protein around day 8 to 10 after symptom onset.…”

Section: Inhibition Of Protein Glycosylation To Both Modulate Virus‐amentioning

confidence: 99%

Hyperglycemia, hydroxychloroquine, and the COVID‐19 pandemic

Brufsky

2020

Journal of Medical Virology

172

167

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Coronavirus disease-2019 infection and its severity can be explained by the concentration of glycosylated severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) viral particles in the lung epithelium, the concentration of glycosylated angiotensin-converting enzyme receptor 2 (ACE2) in the lung epithelium, and the degree and control of the pulmonary immune response to the SARS-CoV-2 spike protein at approximately day 8 to 10 after symptom onset, which may be related to both. Binding of ACE2 by SARS-CoV-2 in COVID-19 also suggests that prolonged uncontrolled hyperglycemia, and not just a history of diabetes mellitus, may be important in the pathogenesis of the disease. It is tempting to consider that the same mechanism acts in COVID-19 as in SARS, where an overactive macrophage M1 inflammatory response, as neutralizing antibodies to the SARS-CoV-2 spike protein form at day 7 to 10, results in acute respiratory distress syndrome (ARDS) in susceptible patients. It also allows consideration of agents, such as hydroxychloroquine, which may interfere with this overly brisk macrophage inflammatory response and perhaps influence the course of the disease, in particular, those that blunt but do not completely abrogate the M1 to M2 balance in macrophage polarization, as well as viral load, which in SARS appears to be temporally related to the onset of ARDS. K E Y W O R D S antibody-mediated cell-mediated cytotoxicity, antiviral agents, SARS coronavirus lium, the concentration of glycosylated angiotensin-converting enzyme ---This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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“…However, we have shown in previous investigations of drug effects on macrophage polarization that pharmacological agents can mediate macrophage phenotype changes without modifying all the expected markers in the same way. 25,37 This is not surprising on the basis of their different mechanisms of action.…”

Section: Discussionmentioning

confidence: 99%

“…to MdMs by addition of GM-CSF. To characterize the inflammatory status of the cells, surface markers that are up-regulated during differentiation (CD80, CD86, CD163, CD206, TREM2, HLA-DR) and cytokines that are released during differentiation (IL-10, IL-6, CCL18, CCL17) 25 were determined. CD163, an immune sensor for bacteria, was significantly increased at 5 nmol/L silvestrol, whereas the pattern recognition receptor CD206 and TREM2 were significantly reduced ( Figure 1D).…”

Section: Silvestrol Modifies Differentiation Of Mdmmentioning

confidence: 99%

Natural antiviral compound silvestrol modulates human monocyte‐derived macrophages and dendritic cells

Blum

Geißlinger

Parnham

et al. 2020

J Cellular Molecular Medi

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Over the last few years, we have had to face several severe virus-mediated disease outbreaks like the current worldwide Sars-CoV-2 pandemic, the Ebola virus outbreak in West Africa and the Zika virus outbreak in South America. The treatment options for virus-mediated diseases are limited, so well-tolerated as well as efficient antiviral therapies are urgently needed. 1 The use of the natural compound silvestrol is a promising new broad-spectrum approach for the treatment of viral infections. Silvestrol can be isolated from the plants of the genus Aglaia 2 and was initially described in the field of cancer research where it showed potent anti-tumour activity in vivo and in vitro. 3-5 The effects of silvestrol are based on the highly specific inhibition of the ATP-dependent DEAD-box RNA helicase eIF4A. 6,7 Several viruses rely on this host factor for the translation of their mRNAs. The targeting of host factors has advantages, like a Abstract Outbreaks of infections with viruses like Sars-CoV-2, Ebola virus and Zika virus lead to major global health and economic problems because of limited treatment options. Therefore, new antiviral drug candidates are urgently needed. The promising new antiviral drug candidate silvestrol effectively inhibited replication of Corona-, Ebola-, Zika-, Picorna-, Hepatis E and Chikungunya viruses. Besides a direct impact on pathogens, modulation of the host immune system provides an additional facet to antiviral drug development because suitable immune modulation can boost innate defence mechanisms against the pathogens. In the present study, silvestrol down-regulated several pro-and anti-inflammatory cytokines (IL-6, IL-8, IL-10, CCL2, CCL18) and increased TNF-α during differentiation and activation of M1-macrophages, suggesting that the effects of silvestrol might cancel each other out. However, silvestrol amplified the anti-inflammatory potential of M2-macrophages by increasing expression of anti-inflammatory surface markers CD206, TREM2 and reducing release of proinflammatory IL-8 and CCL2. The differentiation of dendritic cells in the presence of silvestrol is characterized by down-regulation of several surface markers and cytokines indicating that differentiation is impaired by silvestrol. In conclusion, silvestrol influences the inflammatory status of immune cells depending on the cell type and activation status. K E Y W O R D S antiviral, cytokines, eIF4A, energy metabolism, immune modulation, RNA viruses, rocaglate

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An in vitro test system for compounds that modulate human inflammatory macrophage polarization

Cited by 29 publications

References 51 publications

Low dose of hydroxychloroquine reduces fatality of critically ill patients with COVID-19

Low dose of hydroxychloroquine reduces fatality of critically ill patients with COVID-19

Hyperglycemia, hydroxychloroquine, and the COVID‐19 pandemic

Natural antiviral compound silvestrol modulates human monocyte‐derived macrophages and dendritic cells

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