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

Zhang, F.; Mears, J. R.; Shakib, L.; Beynor, J. I.; Shanaj, S.; Korsunsky, I.; Nathan, A.; Accelerating Medicines Partnership Rheumatoid Arthritis and Systemic Lupus Erythematosus,; Donlin, L. T.; Raychaudhuri, S.

doi:10.1101/2020.08.05.238360

bioRxiv · 10.1101/2020.08.05.238360

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

Zhang, F.·Mears, J. R.·Shakib, L.·Beynor, J. I.·Shanaj, S.·Korsunsky, I.·Nathan, A.·Accelerating Medicines Partnership Rheumatoid Arthritis and Systemic Lupus Erythematosus,·Donlin, L. T.·Raychaudhuri, S.

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Abstract

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. Using an integrative strategy, we built a reference by meta-analyzing > 300,000 immune cells from COVID-19 and 5 inflammatory diseases including rheumatoid arthritis (RA), Crohns disease (CD), ulcerative colitis (UC), lupus, and interstitial lung disease. Our cross-disease analysis revealed that an FCN1+ inflammatory macrophage state is common to COVID-19 bronchoalveolar lavage samples, RA synovium, CD ileum, and UC colon. We also observed that a CXCL10+ CCL2+ inflammatory macrophage state is abundant in severe COVID-19, inflamed CD and RA, and expresses inflammatory genes such as GBP1, STAT1, and IL1B. We found that the CXCL10+ CCL2+ macrophages are transcriptionally similar to blood-derived macrophages stimulated with TNF- and IFN-{gamma} ex vivo. Our findings suggest that IFN-{gamma}, alongside TNF-, might be a key driver of this abundant inflammatory macrophage phenotype in severe COVID-19 and other inflammatory diseases, which may be targeted by existing immunomodulatory therapies.

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Zhang, F., Mears, J. R., Shakib, L., Beynor, J. I., Shanaj, S., Korsunsky, I., Nathan, A., Accelerating Medicines Partnership Rheumatoid Arthritis and Systemic Lupus Erythematosus,, Donlin, L. T., Raychaudhuri, S.. 2020-08-05. IFN-γ and TNF-α drive a CXCL10+ CCL2+ macrophage phenotype expanded in severe COVID-19 and other diseases with tissue inflammation. https://doi.org/10.1101/2020.08.05.238360

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