IFN-γ and TNF-α drive a CXCL10+ CCL2+ macrophage phenotype expanded in severe COVID-19 lungs and inflammatory diseases with tissue inflammation
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Abstract
Background
Immunosuppressive and anti-cytokine treatment may have a protective effect for patients with COVID-19. Understanding the immune cell states shared between COVID-19 and other inflammatory diseases with established therapies may help nominate immunomodulatory therapies.
Methods
To identify cellular phenotypes that may be shared across tissues affected by disparate inflammatory diseases, we developed a meta-analysis and integration pipeline that models and removes the effects of technology, tissue of origin, and donor that confound cell-type identification. Using this approach, we integrated > 300,000 single-cell transcriptomic profiles from COVID-19-affected lungs and tissues from healthy subjects and patients with five inflammatory diseases: rheumatoid arthritis (RA), Crohn’s disease (CD), ulcerative colitis (UC), systemic lupus erythematosus (SLE), and interstitial lung disease. We tested the association of shared immune states with severe/inflamed status compared to healthy control using mixed-effects modeling. To define environmental factors within these tissues that shape shared macrophage phenotypes, we stimulated human blood-derived macrophages with defined combinations of inflammatory factors, emphasizing in particular antiviral interferons IFN-beta (IFN-β) and IFN-gamma (IFN-γ), and pro-inflammatory cytokines such as TNF.
Results
We built an immune cell reference consisting of > 300,000 single-cell profiles from 125 healthy or disease-affected donors from COVID-19 and five inflammatory diseases. We observed a CXCL10+ CCL2+ inflammatory macrophage state that is shared and strikingly abundant in severe COVID-19 bronchoalveolar lavage samples, inflamed RA synovium, inflamed CD ileum, and UC colon. These cells exhibited a distinct arrangement of pro-inflammatory and interferon response genes, including elevated levels of CXCL10 , CXCL9 , CCL2 , CCL3 , GBP1, STAT1 , and IL1B . Further, we found this macrophage phenotype is induced upon co-stimulation by IFN-γ and TNF-α.
Conclusions
Our integrative analysis identified immune cell states shared across inflamed tissues affected by inflammatory diseases and COVID-19. Our study supports a key role for IFN-γ together with TNF-α in driving an abundant inflammatory macrophage phenotype in severe COVID-19-affected lungs, as well as inflamed RA synovium, CD ileum, and UC colon, which may be targeted by existing immunomodulatory therapies.
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SciScore for 10.1101/2020.08.05.238360: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Table 2: Resources
No key resources detected.
Results from OddPub: Thank you for sharing your code.
Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04337359 No longer available Ruxolitinib Managed Access Program (MAP) for Patients Diagno… NCT04359290 Active, not recruiting Ruxolitinib for Treatment … SciScore for 10.1101/2020.08.05.238360: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Table 2: Resources
No key resources detected.
Results from OddPub: Thank you for sharing your code.
Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04337359 No longer available Ruxolitinib Managed Access Program (MAP) for Patients Diagno… NCT04359290 Active, not recruiting Ruxolitinib for Treatment of Covid-19 Induced Lung Injury AR… NCT04348695 Recruiting Study of Ruxolitinib Plus Simvastatin in the Prevention and … Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
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SciScore for 10.1101/2020.08.05.238360: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
Experimental Models: Organisms/Strains Sentences Resources trea IFN IL FNh fi h fibTN rea IFN IL t d i t ti it wi wi Un an w w w Un -γ -α α -γ α F- IFN FFN TNF N I T nd a -α F TN CCL23 15 4 2 0 Fold change, TNF-α (vs untreated) f CCL2 IDO1 CXCL10 AN MRC1 4 3 2 1 0 P9 3 2 1 0 1A CXCL9 CLEC4A 3 2 1 0 ● ● γ o γ γ α d N- fibr fibro F- ate N-β L-4 N- ro - ro ro -α ed -β 4 N I IF fib FN ib ib F at N Lth ith T ntre IF d ith I ith f ith f TNtre IF I n w a w U Un α α γwαw F- N-γ w w w Un -γ -α α -γ α F-suggested: NoneRes…
SciScore for 10.1101/2020.08.05.238360: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
Experimental Models: Organisms/Strains Sentences Resources trea IFN IL FNh fi h fibTN rea IFN IL t d i t ti it wi wi Un an w w w Un -γ -α α -γ α F- IFN FFN TNF N I T nd a -α F TN CCL23 15 4 2 0 Fold change, TNF-α (vs untreated) f CCL2 IDO1 CXCL10 AN MRC1 4 3 2 1 0 P9 3 2 1 0 1A CXCL9 CLEC4A 3 2 1 0 ● ● γ o γ γ α d N- fibr fibro F- ate N-β L-4 N- ro - ro ro -α ed -β 4 N I IF fib FN ib ib F at N Lth ith T ntre IF d ith I ith f ith f TNtre IF I n w a w U Un α α γwαw F- N-γ w w w Un -γ -α α -γ α F-suggested: NoneResults from OddPub: Thank you for sharing your code.
Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.
Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
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