COVID-19 and RA share an SPP1 myeloid pathway that drives PD-L1+ neutrophils and CD14+ monocytes
Lucy MacDonald, Stefano Alivernini, Barbara Tolusso, Aziza Elmesmari, Domenico Somma, Simone Perniola, Annamaria Paglionico, Luca Petricca, Silvia L. Bosello, Angelo Carfì, Michela Sali, Egidio Stigliano, Antonella Cingolani, Rita Murri, Vincenzo Arena, Massimo Fantoni, Massimo Antonelli, Francesco Landi, Francesco Franceschi, Maurizio Sanguinetti, Iain B. McInnes, Charles McSharry, Antonio Gasbarrini, Thomas D. Otto, Mariola Kurowska-Stolarska, Elisa Gremese
Lucy MacDonald, Stefano Alivernini, Barbara Tolusso, Aziza Elmesmari, Domenico Somma, Simone Perniola, Annamaria Paglionico, Luca Petricca, Silvia L. Bosello, Angelo Carfì, Michela Sali, Egidio Stigliano, Antonella Cingolani, Rita Murri, Vincenzo Arena, Massimo Fantoni, Massimo Antonelli, Francesco Landi, Francesco Franceschi, Maurizio Sanguinetti, Iain B. McInnes, Charles McSharry, Antonio Gasbarrini, Thomas D. Otto, Mariola Kurowska-Stolarska, Elisa Gremese
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Research Article Infectious disease Inflammation

COVID-19 and RA share an SPP1 myeloid pathway that drives PD-L1+ neutrophils and CD14+ monocytes

Abstract

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.

Authors

Lucy MacDonald, Stefano Alivernini, Barbara Tolusso, Aziza Elmesmari, Domenico Somma, Simone Perniola, Annamaria Paglionico, Luca Petricca, Silvia L. Bosello, Angelo Carfì, Michela Sali, Egidio Stigliano, Antonella Cingolani, Rita Murri, Vincenzo Arena, Massimo Fantoni, Massimo Antonelli, Francesco Landi, Francesco Franceschi, Maurizio Sanguinetti, Iain B. McInnes, Charles McSharry, Antonio Gasbarrini, Thomas D. Otto, Mariola Kurowska-Stolarska, Elisa Gremese

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Figure 6

SPP1 stimulation drives proinflammatory CD14+ monocyte and CD274+ (PD-L1+) neutrophil phenotypes.

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SPP1 stimulation drives proinflammatory CD14+ monocyte and CD274+ (PD-L1...
Whole blood cells from healthy donors (n = 3) were stimulated with SPP1 (50 or 200 ng/mL) or were unstimulated, for 16 hours. (A) UMAP of 13,580 integrated control and SPP1-stimulated blood cells colored by cluster identity. (B) Stacked bar plot illustrating cluster proportion of total whole blood cells per condition/dose of SPP1. * P < 0.05, 1-way ANOVA with correction for multiple comparisons. (-), unstimulated control. (C) UMAPs illustrating change in expression of MME (CD10) and CD274 (PD-L1) by neutrophil clusters following SPP1 stimulation. (D) Heatmap showing expression of the top 20 marker genes of each neutrophil phenotype, illustrated as average expression of each gene per sample per condition. Adjusted P < 0.05, MAST with Bonferroni correction. (E) Average of SPP1-driven CD274+ neutrophil gene module score by neutrophil clusters of COVID-19 whole blood cell data set (22). (F) UMAP expression of the SPP1-driven CD274+ neutrophil gene module in COVID-19 whole blood data set. (G) Heatmap showing expression of genes significantly differentially expressed in CD14+ monocytes comparing SPP1 (200 ng/mL) stimulation with unstimulated control, illustrated as average expression of gene per condition. Adjusted P < 0.05, MAST with Bonferroni correction. Red and orange arrows in D and G represent genes regulated by 200 ng/mL only, or by 200 and 50 ng/mL SPP1, respectively.