Journal Article

IFN-γ and TNF-α drive a CXCL10+ CCL2+ macrophage phenotype expanded in severe COVID-19 lungs and inflammatory diseases with tissue inflammation

Nathan, Aparna, Shakib, Lorien, Korsunsky, Ilya, Raychaudhuri, Soumya, Mears, Joseph R., Donlin, Laura T., Zhang, Fan, Shanaj, Sara, Beynor, Jessica I.

2021

Overview

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.

• Publisher: BioMed Central,Springer Nature B.V,BMC
• Subject: Alveoli / Antiviral drugs / Arthritis / Arthritis, Rheumatoid - genetics / Arthritis, Rheumatoid - immunology / Bioinformatics / Biomedical and Life Sciences / Biomedicine / Blood / Bronchoalveolar Lavage Fluid - cytology / Bronchoalveolar Lavage Fluid - immunology / Bronchus / Cancer Research / CCL3 protein / Colitis, Ulcerative - genetics / Colitis, Ulcerative - immunology / Colon / Colon - immunology / Coronaviruses / COVID-19 / COVID-19 - genetics / COVID-19 - immunology / Crohn Disease - genetics / Crohn Disease - immunology / Crohn's disease / CXCL10 protein / Cytokine storm / Cytokines - immunology / Datasets / Environmental factors / Gene expression / Genotype & phenotype / Homeostasis / Human Genetics / Humans / Ileum / Immunomodulation / Inflammation / Inflammation - genetics / Inflammation - immunology / Inflammatory bowel diseases / Inflammatory diseases / Interleukin 1 / Kinases / Lung - immunology / Lung diseases / Lung Diseases, Interstitial - genetics / Lung Diseases, Interstitial - immunology / Lungs / Lupus Erythematosus, Systemic - genetics / Lupus Erythematosus, Systemic - immunology / Macrophage heterogeneity / Macrophage stimulation / Macrophages / Macrophages - immunology / Medicine/Public Health / Metabolomics / Monocyte chemoattractant protein 1 / Phenotype / Phenotypes / Principal components analysis / Rheumatoid arthritis / RNA-Seq / SARS-CoV-2 / Single-cell multi-disease tissue integration / Single-cell transcriptomics / Small intestine / Stat1 protein / Synovium / Systemic lupus erythematosus / Systems Biology / Tumor necrosis factor-TNF / Tumor necrosis factor-α / Ulcerative colitis / β-Interferon / γ-Interferon