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 BALF macrophage clusters FCN1pos and FCN1posSPP1pos predominant in severe COVID-19 were transcriptionally related to synovial tissue macrophage (STM) clusters CD48highS100A12pos and CD48posSPP1pos that drive Rheumatoid Arthritis (RA) synovitis. BALF macrophage cluster FABP4pos predominant in healthy lung was transcriptionally related to STM cluster TREM2pos 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 remained high in post-COVID-19 stage. High plasma levels of SPP1 were unique to severe COVID-19 when compared to other causes of severe pneumonia, and immunohistochemistry localized SPP1pos macrophages in the alveoli of COVID-19 lung. Investigation into SPP1 mechanisms of action revealed that it drives pro-inflammatory activation of CD14pos monocytes and development of PD-L1pos 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 monitoring.


© 2021 MacDonald et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Cite as

MacDonald, L., Alivernini, S., Tolusso, B., Elmesmari, A., Somma, D., Perniola, S., Paglionico, A., Petricca, L., Bosello, S., Carfì, A., Sali, M., Stigliano, E., Cingolani, A., Murri, R., Arena, V., Fantoni, M., Antonelli, M., Landi, F., Franceschi, F., Sanguinetti, M., McInnes, I., McSharry, C., Gasbarrini, A., Otto, T., Kurowska-Stolarska, M. & Gremese, E. 2021, 'COVID-19 and RA share SPP1 myeloid pathway that drives PD-L1pos neutrophils and CD14pos monocytes', JCI Insight, 6(13), article no: e147413. https://doi.org/10.1172/jci.insight.147413

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Last updated: 16 June 2022
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