TY - JOUR AU - MacDonald, Lucy AU - Alivernini, Stefano AU - Tolusso, Barbara AU - Elmesmari, Aziza AU - Somma, Domenico AU - Perniola, Simone AU - Paglionico, Annamaria AU - Petricca, Luca AU - Bosello, Silvia L. AU - Carfì, Angelo AU - Sali, Michela AU - Stigliano, Egidio AU - Cingolani, Antonella AU - Murri, Rita AU - Arena, Vincenzo AU - Fantoni, Massimo AU - Antonelli, Massimo AU - Landi, Francesco AU - Franceschi, Francesco AU - Sanguinetti, Maurizio AU - McInnes, Iain B. AU - McSharry, Charles AU - Gasbarrini, Antonio AU - Otto, Thomas D. AU - Kurowska-Stolarska, Mariola AU - Gremese, Elisa T1 - COVID-19 and RA share an SPP1 myeloid pathway that drives PD-L1+ neutrophils and CD14+ monocytes PY - 2021/07/08/ AB - We explored the potential link between chronic inflammatory arthritis and COVID-19 pathogenic and resolving macrophage pathways and their role in COVID-19 pathogenesis. We found that bronchoalveolar lavage fluid (BALF) macrophage clusters FCN1+ and FCN1+SPP1+ predominant in severe COVID-19 were transcriptionally related to synovial tissue macrophage (STM) clusters CD48hiS100A12+ and CD48+SPP1+ that drive rheumatoid arthritis (RA) synovitis. BALF macrophage cluster FABP4+ predominant in healthy lung was transcriptionally related to STM cluster TREM2+ that governs resolution of synovitis in RA remission. Plasma concentrations of SPP1 and S100A12 (key products of macrophage clusters shared with active RA) were high in severe COVID-19 and predicted the need for Intensive Care Unit transfer, and they remained high in the post–COVID-19 stage. High plasma levels of SPP1 were unique to severe COVID-19 when compared with other causes of severe pneumonia, and IHC localized SPP1+ macrophages in the alveoli of COVID-19 lung. Investigation into SPP1 mechanisms of action revealed that it drives proinflammatory activation of CD14+ monocytes and development of PD-L1+ neutrophils, both hallmarks of severe COVID-19. In summary, COVID-19 pneumonitis appears driven by similar pathogenic myeloid cell pathways as those in RA, and their mediators such as SPP1 might be an upstream activator of the aberrant innate response in severe COVID-19 and predictive of disease trajectory including post–COVID-19 pathology. JF - JCI Insight JA - JCI Insight SN - 2379-3708 DO - 10.1172/jci.insight.147413 VL - 6 IS - 13 UR - https://doi.org/10.1172/jci.insight.147413 PB - The American Society for Clinical Investigation ER -