Meta-Analysis of in vitro-Differentiated Macrophages Identifies Transcriptomic Signatures That Classify Disease Macrophages in vivo

Chen, Hung Jen; Yim, Andrew Y. Li; Griffith, Guillermo R.; Jonge, Wouter J. de; Mannens, Marcel M.A.M.; Ferrero, Enrico; Henneman, Peter; Winther, Menno P.J. de

doi:10.3389/fimmu.2019.02887

Cited by 36 publications

(33 citation statements)

References 89 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We assessed the effect of anti-spike antibodies from serum of patients who were critically ill COVID-19 on human M2polarized macrophages. Our previous transcriptional analysis revealed that macrophage colony-stimulating factor (M-CSF) plus interleukin (IL)-10 induces M2 monocyte differentiation that generates macrophages that most closely resemble primary human lung macrophages (16). Since activation of immune cells by IgG antibodies requires immune complex formation by binding of IgG to its cognate antigen (17,18), we generated spike-IgG immune complexes by incubating SARS-CoV-2 spike-coated wells with diluted serum from patients with severe COVID-19 treated in the intensive care unit at the Amsterdam University Medical Centers (UMC) that tested positive for anti-SARS-CoV-2 IgG (fig.…”

Section: High Titers Of Anti-spike Igg Promote Inflammation By Alveolar Macrophagesmentioning

confidence: 99%

High titers and low fucosylation of early human anti–SARS-CoV-2 IgG promote inflammation by alveolar macrophages

et al. 2021

Self Cite

View full text Add to dashboard Cite

Patients diagnosed with coronavirus disease 2019 (COVID-19) become critically ill primarily around the time of activation of the adaptive immune response. Here, we provide evidence that antibodies play a role in the worsening of disease at the time of seroconversion. We show that early phase severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) spike protein-specific IgG in serum of critically ill COVID-19 patients induces excessive inflammatory responses by human alveolar macrophages. We identified that this excessive inflammatory response is dependent on two antibody features that are specific for patients with severe COVID-19. First, inflammation is driven by high titers of anti-spike IgG, a hallmark of severe disease. Second, we found that anti-spike IgG from patients with severe COVID-19 is intrinsically more pro-inflammatory because of different glycosylation, particularly low fucosylation, of the antibody Fc tail. Notably, low fucosylation of anti-spike IgG was normalized in a few weeks after initial infection with SARS-CoV-2, indicating that the increased antibody-dependent inflammation mainly occurs at the time of seroconversion. We identified Fcγ Receptor (FcγR) IIa and FcγRIII as the two primary IgG receptors that are responsible for the induction of key COVID-19-associated cytokines such as interleukin-6 and tumor necrosis factor. In addition, we show that anti-spike IgG-activated human macrophages can subsequently break pulmonary endothelial barrier integrity and induce microvascular thrombosis in vitro. Finally, we demonstrate that the inflammatory response induced by anti-spike IgG can be specifically counteracted by fostamatinib, an FDA- and EMA-approved therapeutic small molecule inhibitor of Syk kinase.

show abstract

Section: High Titers Of Anti-spike Igg Promote Inflammation By Alveolar Macrophagesmentioning

confidence: 99%

High titers and low fucosylation of early human anti–SARS-CoV-2 IgG promote inflammation by alveolar macrophages

et al. 2021

Self Cite

View full text Add to dashboard Cite

show abstract

“…We assessed the effect of anti-Spike antibodies from serum of critically ill COVID-19 patients on human M2 macrophages. While different protocols are available for generating human M2 macrophages, our previous transcriptional analyses demonstrated that an M-CSF and IL-10-induced monocyte differentiation protocol generates cells that most closely resemble primary human lung macrophages (14). Since activation of immune cells by IgG antibodies is known to require immune complex formation by binding of IgG to its ligand (15,16), we generated Spike-IgG immune complexes by incubating SARS-CoV-2 Spike-coated wells with diluted serum from severely ill COVID-19 patients (i.e.…”

Section: Main Textmentioning

confidence: 99%

“…All the subjects provided written informed consent prior to donation to Sanquin. Monocytes were isolated from the Buffy coats through density centrifugation using Lymphoprep™ (Axis-Shield) followed by human CD14 magnetic beads purification with the MACS ® cell separation columns (Miltenyi) as previously described (14). The resulting monocytes were seeded on tissue culture plates and subsequently differentiated to macrophages for 6 days in the presence of 50ng/mL human M-CSF (Miltenyi) with Iscove's Modified Dulbecco's Medium (IMDM, Lonza) containing 5% fetal bovine serum (FBS) (Biowest) and 86µg/mL gentamicin (Gibco).…”

Section: Fundingmentioning

confidence: 99%

Anti-SARS-CoV-2 IgG from severely ill COVID-19 patients promotes macrophage hyper-inflammatory responses

Hoepel

Chen

Allahverdiyeva

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

For yet unknown reasons, severely ill COVID-19 patients often become critically ill around the time of activation of adaptive immunity. Here, we show that anti-Spike IgG from serum of severely ill COVID-19 patients induces a hyper-inflammatory response by human macrophages, which subsequently breaks pulmonary endothelial barrier integrity and induces microvascular thrombosis. The excessive inflammatory capacity of this anti-Spike IgG is related to glycosylation changes in the IgG Fc tail. Moreover, the hyper-inflammatory response induced by anti-Spike IgG can be specifically counteracted in vitro by use of the active component of fostamatinib, an FDA- and EMA-approved therapeutic small molecule inhibitor of Syk.One sentence summaryAnti-Spike IgG promotes hyper-inflammation.

show abstract

“…LPS stimulation intensity could significantly affect the gene expression profile and polarization state of macrophages. Compared with short exposure (2–4 h) to LPS, short exposure (18–24 h) to LPS increases the expression of M2-related genes, including the tyrosine protein kinase MER and arginase in macrophages (Chen et al, 2019 ). Further study is needed to explore the regulatory effect of a high concentration of LPS on the polarization state of PAMs.…”

Section: Resultsmentioning

confidence: 99%

“…However, the gene reprogramming and polarization states of macrophages are also affected by stimulation intensity and tissue origin. A meta-analysis of in vitro differentiated macrophages showed that macrophages display distinguishing activation states even after early (2–4 h) or late (18–24 h) LPS infection (Chen et al, 2019 ). In M1-type AMs, increased levels of reactive oxygen species, such as hydrogen peroxide, superoxide, and hydroxyl, are implicated in DNA damage and membrane dysfunction (Riazanski et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Transcriptome Analysis of Selenium-Treated Porcine Alveolar Macrophages Against Lipopolysaccharide Infection

et al. 2021

View full text Add to dashboard Cite

Meta-Analysis of in vitro-Differentiated Macrophages Identifies Transcriptomic Signatures That Classify Disease Macrophages in vivo

Cited by 36 publications

References 89 publications

High titers and low fucosylation of early human anti–SARS-CoV-2 IgG promote inflammation by alveolar macrophages

High titers and low fucosylation of early human anti–SARS-CoV-2 IgG promote inflammation by alveolar macrophages

Anti-SARS-CoV-2 IgG from severely ill COVID-19 patients promotes macrophage hyper-inflammatory responses

Transcriptome Analysis of Selenium-Treated Porcine Alveolar Macrophages Against Lipopolysaccharide Infection

Contact Info

Product

Resources

About