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 3

High levels of SPP1 and S100A12 are associated with a severe COVID-19 disease trajectory.

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High levels of SPP1 and S100A12 are associated with a severe COVID-19 di...
(A) Patients and healthy donors, shown as the following: n = 121 patients with acute pneumonia (n = 29 community acquired SARS-CoV-2– pneumonia, n = 29 mild/moderate COVID-19, n = 63 severe COVID-19), convalescent COVID-19 (n = 41), and healthy controls (n = 10). Representative images of lung CT scans. (B) Plasma levels of SPP1, S100A12, GAS6, and PROS1 in groups as in A. (C) Spearman’s rank correlations between SPP1, S100A12, GAS6, and PROS1 plasma levels in patients with acute COVID-19 pneumonia (n = 92) with demographic and clinical parameters. Each box displays the r value, and an asterisk indicates statistical significance of P < 0.05. (D) Plasma levels of SPP1, S100A12, GAS6, and PROS1 in patients with acute COVID-19 pneumonia (n = 92) stratified based on lung functions measured by PaO2/FiO2 at the time of hospital admission. Severe respiratory failure was defined by PaO2/FiO2 ≤ 200. (E) Percentage of acute COVID-19 pneumonia patients (n = 92) with PaO2/FiO2 ≤ 200 based on high plasma levels of SPP1 (≥108 ng/mL), S100A12 (≥59 ng/mL), GAS6 (≥24 ng/mL), and PROS1 (≥15 μg/mL). (F) COVID-19 patient plasma levels of SPP1, S100A12, GAS6, and PROS1 at the time of hospital admission (n = 92) stratified based on a patient’s subsequent need to be transferred to ICU. (G) Percentage of patients with acute COVID-19 pneumonia (n = 92) transferred to ICU during the hospitalization based on having high levels of SPP1 (≥108 ng/mL), S100A12 (≥59 ng/mL), GAS6 (≥24 ng/mL), and PROS1 (≥15 μg/mL) at the time of hospital admission. (B, D, and F) Data are presented as violin plots with median and interquartile range. Asterisk indicates 1-way ANOVA (Kruskal-Wallis test) with Dunn’s correction for multiple comparisons if more than 2 groups were compared (B), or 2-sided Mann-Whitney U was used when 2 groups were compared (B and D–G). (H) Kaplan-Meier analysis of the rate of transfer of COVID-19 patients to ICU based on their cut-off values for SPP1, S100A12, GAS6, and PROS1 at the time of hospital admission.