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1.
Sci Immunol ; 7(68): eabf2846, 2022 02 11.
Article in English | MEDLINE | ID: covidwho-1685480

ABSTRACT

Macrophages regulate protective immune responses to infectious microbes, but aberrant macrophage activation frequently drives pathological inflammation. To identify regulators of vigorous macrophage activation, we analyzed RNA-seq data from synovial macrophages and identified SLAMF7 as a receptor associated with a superactivated macrophage state in rheumatoid arthritis. We implicated IFN-γ as a key regulator of SLAMF7 expression and engaging SLAMF7 drove a strong wave of inflammatory cytokine expression. Induction of TNF-α after SLAMF7 engagement amplified inflammation through an autocrine signaling loop. We observed SLAMF7-induced gene programs not only in macrophages from rheumatoid arthritis patients but also in gut macrophages from patients with active Crohn's disease and in lung macrophages from patients with severe COVID-19. This suggests a central role for SLAMF7 in macrophage superactivation with broad implications in human disease pathology.


Subject(s)
Inflammation/immunology , Macrophage Activation/immunology , Signaling Lymphocytic Activation Molecule Family/immunology , Transcriptome/immunology , Acute Disease , Adult , Arthritis, Rheumatoid/genetics , Arthritis, Rheumatoid/immunology , Arthritis, Rheumatoid/metabolism , COVID-19/genetics , COVID-19/immunology , COVID-19/metabolism , COVID-19/virology , Cells, Cultured , Chronic Disease , Crohn Disease/genetics , Crohn Disease/immunology , Crohn Disease/metabolism , Female , Humans , Inflammation/genetics , Inflammation/metabolism , Macrophage Activation/genetics , RNA-Seq/methods , Reverse Transcriptase Polymerase Chain Reaction/methods , SARS-CoV-2/immunology , SARS-CoV-2/physiology , Signaling Lymphocytic Activation Molecule Family/genetics , Signaling Lymphocytic Activation Molecule Family/metabolism , Single-Cell Analysis/methods , Synovial Membrane/immunology , Synovial Membrane/metabolism , Synovial Membrane/pathology , Transcriptome/genetics
2.
Clin Sci (Lond) ; 135(22): 2559-2573, 2021 11 26.
Article in English | MEDLINE | ID: covidwho-1541262

ABSTRACT

Granulocyte macrophage colony stimulating factor (GM-CSF) is a key participant in, and a clinical target for, the treatment of inflammatory diseases including rheumatoid arthritis (RA). Therapeutic inhibition of GM-CSF signalling using monoclonal antibodies to the α-subunit of the GM-CSF receptor (GMCSFRα) has shown clear benefit in patients with RA, giant cell arteritis (GCAs) and some efficacy in severe SARS-CoV-2 infection. However, GM-CSF autoantibodies are associated with the development of pulmonary alveolar proteinosis (PAP), a rare lung disease characterised by alveolar macrophage (AM) dysfunction and the accumulation of surfactant lipids. We assessed how the anti-GMCSFRα approach might impact surfactant turnover in the airway. Female C57BL/6J mice received a mouse-GMCSFRα blocking antibody (CAM-3003) twice per week for up to 24 weeks. A parallel, comparator cohort of the mouse PAP model, GM-CSF receptor ß subunit (GMCSFRß) knock-out (KO), was maintained up to 16 weeks. We assessed lung tissue histopathology alongside lung phosphatidylcholine (PC) metabolism using stable isotope lipidomics. GMCSFRß KO mice reproduced the histopathological and biochemical features of PAP, accumulating surfactant PC in both broncho-alveolar lavage fluid (BALF) and lavaged lung tissue. The incorporation pattern of methyl-D9-choline showed impaired catabolism and not enhanced synthesis. In contrast, chronic supra-pharmacological CAM-3003 exposure (100 mg/kg) over 24 weeks did not elicit a histopathological PAP phenotype despite some changes in lung PC catabolism. Lack of significant impairment of AM catabolic function supports clinical observations that therapeutic antibodies to this pathway have not been associated with PAP in clinical trials.


Subject(s)
Arthritis, Rheumatoid/metabolism , COVID-19/therapy , Pulmonary Alveolar Proteinosis/immunology , Pulmonary Surfactants/metabolism , Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/antagonists & inhibitors , Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/metabolism , Animals , Antibodies, Monoclonal, Humanized/pharmacology , Arthritis, Rheumatoid/therapy , Autoantibodies/chemistry , Bronchoalveolar Lavage Fluid , COVID-19/immunology , Choline/analogs & derivatives , Female , Granulocyte-Macrophage Colony-Stimulating Factor/chemistry , Inflammation , Interleukin-6/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Phenotype , Pulmonary Alveolar Proteinosis/genetics , SARS-CoV-2/immunology , Surface-Active Agents
3.
Clin Sci (Lond) ; 135(22): 2559-2573, 2021 11 26.
Article in English | MEDLINE | ID: covidwho-1517650

ABSTRACT

Granulocyte macrophage colony stimulating factor (GM-CSF) is a key participant in, and a clinical target for, the treatment of inflammatory diseases including rheumatoid arthritis (RA). Therapeutic inhibition of GM-CSF signalling using monoclonal antibodies to the α-subunit of the GM-CSF receptor (GMCSFRα) has shown clear benefit in patients with RA, giant cell arteritis (GCAs) and some efficacy in severe SARS-CoV-2 infection. However, GM-CSF autoantibodies are associated with the development of pulmonary alveolar proteinosis (PAP), a rare lung disease characterised by alveolar macrophage (AM) dysfunction and the accumulation of surfactant lipids. We assessed how the anti-GMCSFRα approach might impact surfactant turnover in the airway. Female C57BL/6J mice received a mouse-GMCSFRα blocking antibody (CAM-3003) twice per week for up to 24 weeks. A parallel, comparator cohort of the mouse PAP model, GM-CSF receptor ß subunit (GMCSFRß) knock-out (KO), was maintained up to 16 weeks. We assessed lung tissue histopathology alongside lung phosphatidylcholine (PC) metabolism using stable isotope lipidomics. GMCSFRß KO mice reproduced the histopathological and biochemical features of PAP, accumulating surfactant PC in both broncho-alveolar lavage fluid (BALF) and lavaged lung tissue. The incorporation pattern of methyl-D9-choline showed impaired catabolism and not enhanced synthesis. In contrast, chronic supra-pharmacological CAM-3003 exposure (100 mg/kg) over 24 weeks did not elicit a histopathological PAP phenotype despite some changes in lung PC catabolism. Lack of significant impairment of AM catabolic function supports clinical observations that therapeutic antibodies to this pathway have not been associated with PAP in clinical trials.


Subject(s)
Arthritis, Rheumatoid/metabolism , COVID-19/therapy , Pulmonary Alveolar Proteinosis/immunology , Pulmonary Surfactants/metabolism , Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/antagonists & inhibitors , Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/metabolism , Animals , Antibodies, Monoclonal, Humanized/pharmacology , Arthritis, Rheumatoid/therapy , Autoantibodies/chemistry , Bronchoalveolar Lavage Fluid , COVID-19/immunology , Choline/analogs & derivatives , Female , Granulocyte-Macrophage Colony-Stimulating Factor/chemistry , Inflammation , Interleukin-6/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Phenotype , Pulmonary Alveolar Proteinosis/genetics , SARS-CoV-2/immunology , Surface-Active Agents
4.
JCI Insight ; 6(13)2021 06 18.
Article in English | MEDLINE | ID: covidwho-1346128

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.


Subject(s)
Arthritis, Rheumatoid/immunology , COVID-19/immunology , Monocytes/immunology , Neutrophils/immunology , Osteopontin/immunology , Arthritis, Rheumatoid/metabolism , B7-H1 Antigen/immunology , Bronchoalveolar Lavage Fluid/immunology , CD48 Antigen/immunology , COVID-19/chemically induced , COVID-19/metabolism , Fatty Acid-Binding Proteins/immunology , Humans , Lectins/immunology , Lipopolysaccharide Receptors/immunology , Lipopolysaccharide Receptors/metabolism , Lung/diagnostic imaging , Lung/immunology , Lung/metabolism , Lung/pathology , Macrophages/immunology , Macrophages/metabolism , Membrane Glycoproteins/immunology , Monocytes/metabolism , Neutrophils/metabolism , Osteopontin/blood , Receptor Protein-Tyrosine Kinases/metabolism , Receptors, Immunologic/immunology , S100A12 Protein/immunology , S100A12 Protein/metabolism , Synovial Membrane/immunology , Tomography, X-Ray Computed
5.
Eur J Immunol ; 51(9): 2330-2340, 2021 09.
Article in English | MEDLINE | ID: covidwho-1261763

ABSTRACT

The molecular mechanism of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Spike protein was characterized to identify novel therapies. The impact of tofacitinib, IL-6R Ab, or TNFi therapy was determined on Spike protein or LPS/IFN-γ-induced signaling, inflammation, and metabolic reprogramming in MΦs and/or rheumatoid arthritis (RA) fibroblast-like synoviocyte (FLS). ACE2 frequency was markedly expanded in MΦs compared to T cells and RA FLS. Tofacitinib suppresses Spike protein potentiated STAT1 signaling, whereas this function was unchanged by TNFi. Tofacitinib impairs IL-6/IFN/LPS-induced STAT1 and STAT3 phosphorylation in RA MΦs and FLS. Interestingly, tofacitinib had a broader inhibitory effect on the monokines, glycolytic regulators, or oxidative metabolites compared to IL-6R Ab and TNFi in Spike-protein-activated MΦs. In contrast, all three therapies disrupted IFN-α and IFN-ß secretion in response to Spike protein; nonetheless, the IFN-γ was only curtailed by tofacitinib or IL-6R Ab. While tofacitinib counteracted MΦ metabolic rewiring instigated by Spike protein, it was inconsequential on the glycolysis expansion mediated via HK2 and/or LDHA in the activated RA MΦ and FLS. Nevertheless, the potentiated inflammatory response and the diminished oxidative phosphorylation modulated by Spike protein and/or LPS/IFN-γ stimulation in MΦs or RA FLS were reversed by tofacitinib. In conclusion, tofacitinib suppresses MΦ inflammation and immunometabolism triggered by Spike protein and may provide a promising strategy for COVID-19 patients.


Subject(s)
COVID-19/drug therapy , Macrophages/drug effects , Piperidines/pharmacology , Pyrimidines/pharmacology , SARS-CoV-2/drug effects , Spike Glycoprotein, Coronavirus/metabolism , Arthritis, Rheumatoid/metabolism , COVID-19/metabolism , Cells, Cultured , Fibroblasts/drug effects , Fibroblasts/metabolism , Humans , Interleukin-6/metabolism , Macrophages/metabolism , Receptors, Interleukin-6/metabolism , STAT1 Transcription Factor/metabolism , STAT3 Transcription Factor/metabolism , Signal Transduction/drug effects , Tumor Necrosis Factor-alpha/metabolism
6.
Sci Rep ; 11(1): 2512, 2021 01 28.
Article in English | MEDLINE | ID: covidwho-1054059

ABSTRACT

Whenever some phenomenon can be represented as a graph or a network it seems pertinent to explore how much the mathematical properties of that network impact the phenomenon. In this study we explore the same philosophy in the context of immunology. Our objective was to assess the correlation of "size" (number of edges and minimum vertex cover) of the JAK/STAT network with treatment effect in rheumatoid arthritis (RA), phenotype of viral infection and effect of immunosuppressive agents on a system infected with the coronavirus. We extracted the JAK/STAT pathway from Kyoto Encyclopedia of Genes and Genomes (KEGG, hsa04630). The effects of the following drugs, and their combinations, commonly used in RA were tested: methotrexate, prednisolone, rituximab, tocilizumab, tofacitinib and baricitinib. Following viral systems were also tested for their ability to evade the JAK/STAT pathway: Measles, Influenza A, West Nile virus, Japanese B virus, Yellow Fever virus, respiratory syncytial virus, Kaposi's sarcoma virus, Hepatitis B and C virus, cytomegalovirus, Hendra and Nipah virus and Coronavirus. Good correlation of edges and minimum vertex cover with clinical efficacy were observed (for edge, rho = - 0.815, R2 = 0.676, p = 0.007, for vertex cover rho = - 0.793, R2 = 0.635, p = 0.011). In the viral systems both edges and vertex cover were associated with acuteness of viral infections. In the JAK/STAT system already infected with coronavirus, maximum reduction in size was achieved with baricitinib. To conclude, algebraic and combinatorial invariant of a network may explain its biological behaviour. At least theoretically, baricitinib may be an attractive target for treatment of coronavirus infection.


Subject(s)
Arthritis, Rheumatoid/metabolism , Janus Kinases/metabolism , STAT Transcription Factors/metabolism , Virus Diseases/drug therapy , Virus Diseases/metabolism , Antibodies, Monoclonal, Humanized/pharmacology , Arthritis, Rheumatoid/genetics , Azetidines/pharmacology , Gene Regulatory Networks , Humans , Janus Kinases/genetics , Methotrexate/pharmacology , Models, Statistical , Piperidines/pharmacology , Prednisolone/pharmacology , Purines/pharmacology , Pyrazoles/pharmacology , Pyrimidines/pharmacology , Rituximab/pharmacology , STAT Transcription Factors/genetics , Signal Transduction/drug effects , Sulfonamides/pharmacology
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