COVID-19 and Rheumatoid Arthritis share myeloid pathogenic and resolving pathways
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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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SciScore for 10.1101/2020.07.26.221572: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
Software and Algorithms Sentences Resources The relative proportion of clusters between conditions was explored by exporting tables of percentage of cells in each cluster for each sample and performing statistical analyses using Prism (8.4.2). Prismsuggested: (PRISM, RRID:SCR_005375)The “test.use” function was used to determine genes differentially expressed between clusters within each dataset using MAST. MASTsuggested: (MAST, RRID:SCR_016340)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognize…SciScore for 10.1101/2020.07.26.221572: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
Software and Algorithms Sentences Resources The relative proportion of clusters between conditions was explored by exporting tables of percentage of cells in each cluster for each sample and performing statistical analyses using Prism (8.4.2). Prismsuggested: (PRISM, RRID:SCR_005375)The “test.use” function was used to determine genes differentially expressed between clusters within each dataset using MAST. MASTsuggested: (MAST, RRID:SCR_016340)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04381936 Recruiting Randomised Evaluation of COVID-19 Therapy Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
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