A new study by researchers from the University of Glassgow-Scotland, the Fondazione Policlinico Universitario Agostino Gemelli IRCCS-Italy and the Università Cattolica del Sacro Cuore-Italy has identified that a macrophage induced protein called SPP1 as a mediator that is driving multiple pathogenic inflammatory responses in severe COVID-19 as well as in Long COVID.
The study findings were published in the peer reviewed journal: JCI Insight.
https://insight.jci.org/articles/view/147413
The severity of acute COVID-19 is attributable to genetics, immune dysregulation, abnormal blood clotting and tissue disruption, particularly implicating aberrant proinflammatory and antiviral innate immunity (1–14). Rheumatoid arthritis (RA) represents a proinflammatory cytokine–driven chronic articular condition often accompanied by interstitial lung disease and alveolitis (15).
We (16) and others (17) have reported that SARS-CoV-2 infection is associated with emergence of polyarthritis, or flares of synovitis in RA patients in sustained disease remission, suggesting shared mechanisms of pathogenesis. RA immunopathogenesis and therapeutic targets (18) are well understood and might be informative for COVID-19 therapeutic strategies.
In RA, articular inflammation and remission are driven by distinct synovial tissue macrophage clusters (19). Emerging data suggest that similar aberrant activation of myeloid cells in the blood (7, 20–23) and lung (24, 25) contribute to acute COVID-19 severity.
However, there remains a knowledge gap on myeloid cell pathways that determine the severity and resolution of acute COVID-19 pneumonitis.
In addition, the immune mechanisms of long-lasting clinical sequelae (26) described in convalescent COVID-19 patients are unresolved, hindering development of effective treatments and biomarkers of disease trajectory.
Single-cell profiling and fate-mapping indicate spatial and functional macrophage heterogeneity that maintains lung homeostasis (27–31). Healthy lung alveolar macrophages (AM) expressing Fatty Acid Binding Protein 4 (FABP4) localize to the alveolar epithelial surface and recycle surfactants with type-2 alveolar epithelial cells to maintain compliance and efficient gas exchange (32, 33). This function is compromised in severe COVID-19 (34).
The single-cell RNA sequencing (scRNAseq) analysis (24) of bronchoalveolar lavage fluid (BALF) from severe COVID-19 patients found abnormally low numbers of resident AM and an increase in 2 macrophage clusters that share expression of ficolin-1 (FCN1) and are distinguished by their relative expression of osteopontin (SPP1): FCN1+ and FCN1+SPP1+ clusters.
Their precise roles in the pathogenesis of severe COVID-19 have yet to be established. We recently identified similar macrophage diversity in synovial tissues (ST) of healthy donors and patients with active or remission RA (19).
We delineated in RA chronic synovitis that the CD48hiS100A12+ and CD48+SPP1+ macrophage clusters produced their distinctive pathogenic mediators (S100A12 and SPP1, respectively) in addition to hallmark proinflammatory cytokines IL-6, IL-8, IL-1β, and TNF-α, and activated ST stromal cells.
Early evidence suggested that this serum IL-6, IL-8, IL-1β, and TNF-α cytokine signature also predicts the prognosis of patients with acute COVID-19 (6), and targeting the IL-6 pathway seems an effective therapeutic strategy in critically ill COVID-19 patients (35, 36).
Resolution of synovitis in RA was associated with the functions of a distinct subpopulation of synovial macrophages (TREM2+ and FOLR2+ clusters) that produced abundant lipid resolvins instead of inflammatory mediators and induced a repair phenotype in ST stromal cells (19).
Altogether, this raised the hypothesis that macrophage clusters in the lung, functionally equivalent to those in the synovium, may govern chronic inflammation or resolution of COVID-19 pneumonitis, and that the hallmark cytokine signature related to these clusters (e.g., SPP1) might be a useful biomarker of prognosis and a therapeutic target during the unpredictable trajectory of COVID-19.
