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.
【저자키워드】 Single-cell transcriptomics, Single-cell multi-disease tissue integration, Macrophage stimulation, Macrophage heterogeneity, 【초록키워드】 COVID-19, Treatment, Meta-analysis, Inflammatory diseases, Macrophage, Arthritis, Cytokines, macrophages, severe COVID-19, CXCL10, interferons, lung, Lung disease, Interstitial lung disease, systemic lupus erythematosus, rheumatoid arthritis, inflammatory factors, Patient, understanding, CXCL9, pro-inflammatory cytokines, Integrative analysis, Stat1, interferon response, transcriptomic profile, single-cell, protective effect, IFN-γ, Donor, TNF-α, IFN-gamma, Stimulation, ulcerative colitis, CCL3, association, TNF, Combination, Inflammatory, Immune cell, Crohn’s disease, Immunomodulatory therapies, lupus erythematosus, SLE, Support, human blood-derived macrophages, tissue, tissues, bronchoalveolar lavage samples, CCL2, CD ileum, cellular phenotypes, disease-affected donors, environmental factors, GBP1, healthy control, healthy subjects, IFN-beta, IFN-β, IL1B, immune cell states, inflamed CD ileum, inflamed RA synovium, inflamed tissues, macrophage phenotypes, mixed-effects modeling, RA synovium, severe COVID-19-affected lungs, These cells, UC colon, help, pro-inflammatory cytokine, inflammatory disease, driving, pro-inflammatory, anti-cytokine, Effect, Genes, approach, environmental factor, FIVE, Cell, established therapy, stimulated, Result, defined, tested, identify, affected, healthy, elevated, exhibited, disparate, healthy subject, antiviral interferon, cell-type identification, cellular phenotype, disease-affected donor, human blood-derived macrophage, IFN-beta (IFN-β, immune cell state, immune state, inflamed tissue, inflammatory macrophage phenotype, macrophage phenotype, macrophage state, patients with COVID-19, single-cell profile, 【제목키워드】 severe COVID-19, lung, inflammatory disease, tissue inflammation, macrophage phenotype,