COVID-19 and Rheumatoid Arthritis share myeloid pathogenic and resolving pathways

  1. Lucy MacDonald
  2. Thomas D. Otto
  3. Aziza Elmesmari
  4. Barbara Tolusso
  5. Domenico Somma
  6. Charles McSharry
  7. Elisa Gremese
  8. Iain B. McInnes
  9. Stefano Alivernini
  10. Mariola Kurowska-Stolarska
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Abstract

Background

We recently delineated the functional biology of pathogenic and inflammation resolving synovial tissue macrophage clusters in rheumatoid arthritis (RA). Whilst RA is not a viral respiratory syndrome, it represents a pro-inflammatory cytokine-driven chronic articular condition often accompanied by cardiovascular and lung pathologies. We hypothesised that functionally equivalent macrophage clusters in the lung might govern inflammation and resolution of COVID-19 pneumonitis.

Methods

To provide insight into the targetable functions of COVID-19 bronchoalveolar lavage (BALF) macrophage clusters, a comparative analysis of BALF macrophage single cell transcriptomics (scRNA-seq) with synovial tissue (ST) macrophage scRNA-seq and functional biology was performed. The function of shared BALF and ST MerTK inflammation-resolving pathway was confirmed with inhibitor in primary macrophage-synovial fibroblast co-cultures. Results . Distinct BALF FCN pos and FCN pos SPP1 pos macrophage clusters emerging in severe COVID-19 patients were closely related to ST CD48 high S100A12 pos and CD48 pos SPP1 pos clusters driving synovitis in active RA. They shared transcriptomic profile and pathogenic mechanisms. Healthy lung resident alveolar FABP4 pos macrophages shared a regulatory transcriptomic profile, including TAM (Tyro, Axl, MerTK) receptors pathway with synovial tissue TREM2 pos macrophages that govern RA remission. This pathway was substantially altered in BALF macrophages of severe COVID-19. In vitro dexamethasone inhibited tissue inflammation via macrophages’ MerTK function.

Conclusion

Pathogenesis and resolution of COVID-19 pneumonitis and RA synovitis might be driven by similar macrophage clusters and pathways. The MerTK-dependent anti-inflammatory mechanisms of dexamethasone, and the homeostatic function of TAM pathways that maintain RA in remission advocate the therapeutic MerTK agonism to ameliorate the cytokine storm and pneumonitis of severe COVID-19.

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