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

Lucy MacDonald1, Stefano Alivernini1,2,3, Barbara Tolusso1,3

  • 1Research into Inflammatory Arthritis Centre Versus Arthritis (RACE), University of Glasgow, United Kingdom.

JCI Insight
|June 18, 2021
PubMed

Insights

Severe COVID-19 shares macrophage pathways with rheumatoid arthritis (RA), with specific mediators like SPP1 predicting disease severity and post-COVID-19 complications. Understanding these links aids in managing severe inflammatory responses.

Area of Science:

  • Immunology
  • Pathogenesis of Infectious Diseases
  • Rheumatology

Background:

  • Chronic inflammatory arthritis, such as rheumatoid arthritis (RA), involves dysregulated macrophage activity in synovitis.
  • Severe COVID-19 is characterized by a significant inflammatory response, but the underlying cellular mechanisms are not fully elucidated.
  • Macrophage polarization and function are critical in both inflammatory conditions and host defense.

Purpose of the Study:

  • To investigate the transcriptional relationship between macrophage populations in severe COVID-19 and rheumatoid arthritis.
  • To identify shared pathogenic and resolving macrophage pathways in both conditions.
  • To explore the role of specific macrophage-derived mediators, like SPP1, in COVID-19 pathogenesis and disease trajectory.

Main Methods:

  • Transcriptional profiling of bronchoalveolar lavage fluid (BALF) macrophages from severe COVID-19 patients and synovial tissue macrophages (STM) from RA patients.
  • Comparison of macrophage cluster gene expression profiles between severe COVID-19, healthy controls, and RA patients in different disease states (active synovitis, remission).
  • Measurement of plasma concentrations of key macrophage products (SPP1, S100A12) and immunohistochemical (IHC) localization of SPP1+ macrophages in lung tissue.

Main Results:

  • Macrophage clusters in severe COVID-19 (FCN1+, FCN1+SPP1+) were transcriptionally similar to pathogenic RA STM clusters (CD48hiS100A12+, CD48+SPP1+).
  • Resolving macrophage clusters in healthy lungs (FABP4+) resembled those in RA remission (TREM2+).
  • Elevated plasma SPP1 and S100A12 levels in severe COVID-19 predicted ICU transfer and persisted post-infection. SPP1 was uniquely elevated in severe COVID-19 compared to other pneumonias and localized to lung alveoli.

Conclusions:

  • COVID-19 pneumonitis utilizes similar pathogenic myeloid cell pathways as rheumatoid arthritis.
  • Mediators like SPP1 may act as upstream activators of the aberrant innate immune response in severe COVID-19.
  • These shared pathways and mediators are predictive of disease severity, ICU admission, and post-COVID-19 pathology.
Keywords:
Autoimmune diseasesInfectious diseaseInflammationMacrophages

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