IFN-γ and TNF-α drive a CXCL10+ CCL2+ macrophage phenotype expanded in severe COVID-19 lungs and inflammatory diseases with tissue inflammation. Genome Medicine, 2021


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. 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 5 inflammatory diseases: rheumatoid arthritis (RA), Crohn’s disease (CD), ulcerative colitis (UC), lupus, 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 and IFN-gamma, and pro-inflammatory cytokines such as TNF. We built an immune cell reference consisting of >300,000 single-cell profiles from 125 healthy or disease-affected donors from COVID-19 and 5 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-gamma and TNF-α. 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-gamma 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.

Genome Medicine