Abstract
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.
Highlights
Immunosuppressive and anti-cytokine treatment may have a protective effect for patients with COVID-19
Our study supports a key role for IFN-γ together with tumor necrosis factor (TNF)-α in driving an abundant inflammatory macrophage phenotype in severe COVID-19-affected lungs, as well as inflamed rheumatoid arthritis (RA) synovium, Crohn’s disease (CD) ileum, and ulcerative colitis (UC) colon, which may be targeted by existing immunomodulatory therapies
We demonstrated that the CXCL10+ CCL2+ macrophages from severe COVID-19 lungs share a transcriptional phenotype with macrophages stimulated by TNF-α plus IFN-γ
Summary
Immunosuppressive and anti-cytokine treatment may have a protective effect for patients with COVID-19. A singlecell study of bronchoalveolar lavage fluid (BALF) in intubated COVID-19 patients identified two inflammatory macrophage subsets—one characterized by CCL2, CCL3, and CXCL10 expression and a second by FCN1 and S100A8—as potential mediators of pathology in this late-stage disease [4] The presence of these macrophage subsets in the lung correlated with elevated circulating cytokines and extensive damage to the lung and vascular tissue. Reports looking at peripheral blood from large numbers of COVID-19 patients have consistently documented lymphopenia (reduced lymphocyte frequency) paired with increased levels of CD14+ monocytes and inflammatory cytokines, such as IL1B, TNF-α, IFN-α, and IFN-γ [5,6,7] These factors are ineffective in lowering viral load while possibly contributing to cytokine release syndrome (CRS) [7]. The extent to which these cell states are shared between COVID-19 and other inflammatory diseases and their disease association may further clarify disease mechanisms and precisely define therapeutic targets
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