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

Sara Shanaj¹  Aparna Nathan²  Ilya Korsunsky²  Fan Zhang²  Jessica I. Beynor²  Joseph R. Mears²  Soumya Raychaudhuri³  Lorien Shakib⁴  Laura T. Donlin⁵ 

[1] Arthritis and Tissue Degeneration, Hospital for Special Surgery, New York, NY, USA;Center for Data Sciences, Brigham and Women’s Hospital, 02115, Boston, MA, USA;Division of Genetics, Department of Medicine, Brigham and Women’s Hospital, 02115, Boston, MA, USA;Department of Biomedical Informatics, Harvard Medical School, 02115, Boston, MA, USA;Broad Institute of MIT and Harvard, 02142, Cambridge, MA, USA;Division of Rheumatology, Inflammation, and Immunity, Brigham and Women’s Hospital and Harvard Medical School, 02115, Boston, MA, USA;Center for Data Sciences, Brigham and Women’s Hospital, 02115, Boston, MA, USA;Division of Genetics, Department of Medicine, Brigham and Women’s Hospital, 02115, Boston, MA, USA;Department of Biomedical Informatics, Harvard Medical School, 02115, Boston, MA, USA;Broad Institute of MIT and Harvard, 02142, Cambridge, MA, USA;Division of Rheumatology, Inflammation, and Immunity, Brigham and Women’s Hospital and Harvard Medical School, 02115, Boston, MA, USA;Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, The University of Manchester, Manchester, UK;Graduate Program in Physiology, Biophysics and Systems Biology, Weill Cornell Graduate School of Medical Sciences, 10065, New York, NY, USA;Graduate Program in Physiology, Biophysics and Systems Biology, Weill Cornell Graduate School of Medical Sciences, 10065, New York, NY, USA;Arthritis and Tissue Degeneration, Hospital for Special Surgery, New York, NY, USA;

关键词: Single-cell transcriptomics;    Single-cell multi-disease tissue integration;    COVID-19;    Inflammatory diseases;    Macrophage stimulation;    Macrophage heterogeneity;   

DOI  :  10.1186/s13073-021-00881-3

来源: Springer

【 摘 要 】

BackgroundImmunosuppressive 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.MethodsTo 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.ResultsWe 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.ConclusionsOur 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.

【 授权许可】

CC BY