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PMC:7546716 JSONTXT 17 Projects

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Id Subject Object Predicate Lexical cue
T1 0-65 Sentence denotes Imperfect storm: is interleukin-33 the Achilles heel of COVID-19?
T2 67-75 Sentence denotes Abstract
T3 76-190 Sentence denotes The unique cytokine signature of COVID-19 might provide clues to disease mechanisms and possible future therapies.
T4 191-410 Sentence denotes Here, we propose a pathogenic model in which the alarmin cytokine, interleukin (IL)-33, is a key player in driving all stages of COVID-19 disease (ie, asymptomatic, mild–moderate, severe–critical, and chronic–fibrotic).
T5 411-701 Sentence denotes In susceptible individuals, IL-33 release by damaged lower respiratory cells might induce dysregulated GATA-binding factor 3-expressing regulatory T cells, thereby breaking immune tolerance and eliciting severe acute respiratory syndrome coronavirus 2-induced autoinflammatory lung disease.
T6 702-829 Sentence denotes Such disease might be initially sustained by IL-33-differentiated type-2 innate lymphoid cells and locally expanded γδ T cells.
T7 830-1076 Sentence denotes In severe COVID-19 cases, the IL-33–ST2 axis might act to expand the number of pathogenic granulocyte–macrophage colony-stimulating factor-expressing T cells, dampen antiviral interferon responses, elicit hyperinflammation, and favour thromboses.
T8 1077-1220 Sentence denotes In patients who survive severe COVID-19, IL-33 might drive pulmonary fibrosis by inducing myofibroblasts and epithelial–mesenchymal transition.
T9 1221-1424 Sentence denotes We discuss the therapeutic implications of these hypothetical pathways, including use of therapies that target IL-33 (eg, anti-ST2), T helper 17-like γδ T cells, immune cell homing, and cytokine balance.
T10 1426-1438 Sentence denotes Introduction
T11 1439-1614 Sentence denotes Intensive efforts are underway to unravel the immunopathology of COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and to control the pandemic.
T12 1615-2046 Sentence denotes Given the public health emergency, scarcity of effective antiviral therapies, and rapid evolution of lung disease associated with COVID-19, patients who are critically ill with COVID-19 and have exuberant inflammation, life-threatening acute respiratory distress syndrome, and coagulopathy, are basically treated as if they had secondary haemophagocytic lymphohistiocytosis or virus-associated macrophage activation syndrome (MAS).
T13 2047-2486 Sentence denotes These treatments are focused on therapies that neutralise key cytokines driving classical MAS, such as interleukin-6 ([IL]-6; eg, tocilizumab) or interferon gamma (IFNγ; eg, emapalumab).1, 2 In fact, some fatal cases of COVID-19 are accompanied not only by severe respiratory disease, but also by increased systemic inflammation as shown by higher ferritin concentrations.2 However, in many aspects, COVID-19 does not resemble typical MAS.
T14 2487-2698 Sentence denotes We propose that the cytokine storm syndrome seen in COVID-19 is dissimilar to that seen in canonical MAS and should be regarded as a distinct entity and approached in a novel way reflecting its unique qualities.
T15 2700-2753 Sentence denotes Cellular immunity and T-cell polarisation in COVID-19
T16 2754-3830 Sentence denotes Whereas virus-induced MAS shows the classic hallmarks of a T-helper (Th)-1 profile, with high production of IFNγ,1, 3 COVID-19 is instead characterised by circulating T cells that show an activated Th17 membrane phenotype (CD38+HLA-DR+CD4+CCR6+)4 and express granulocyte–macrophage colony-stimulating factor (GM-CSF) in part along with IFNγ.5 Concentrations of both IL-17 and IFNγ are increased in serum from patients with COVID-19 in proportion with viral load and lung injury.6 Similarly, Middle East respiratory syndrome has been associated with a combined Th1–Th17 inflammatory response.7 Notably, the cytokine storm composition induced by SARS-CoV-2 differs from that induced by severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus, with lower production of type 1 cytokines (eg, IL-12p70, IL-15), and high concentrations of type 2 cytokines (eg, IL-4, IL-9, IL-10, transforming growth factor β [TGFβ], IL-13).6, 7, 8, 9, 10, 11 These findings might provide important clues to the specific immunopathology of COVID-19.
T17 3831-4072 Sentence denotes Transcriptomic analyses of bronchoalveolar lavage fluid from patients with COVID-19 have revealed a strong upregulation of IL-33.11 IL-33 is a cytokine of the IL-1 family that is expressed in barrier tissues and exerts pleiotropic functions.
T18 4073-4901 Sentence denotes In the lungs, IL-33 is promptly released, mainly by injured epithelial alveolar cells, following infection and cellular damage.12 Among its functions, IL-33 enhances TGFβ-mediated differentiation of Foxp3+ regulatory T (Treg) cells13 and stimulates CD11c+ myeloid dendritic cells to secrete IL-2, which drives Treg cell expansion, thus ultimately promoting resolution of inflammation.14 Individuals infected with SARS-CoV-2 who develop milder symptoms tend to have large numbers of Treg cells10 and alveolar macrophages showing a scavenger resolving (FABP4+) phenotype.15 In the presence of an adequate immune response and virus clearance, IL-33 might drive rapid Treg cell-dependent restoration of respiratory tissue homoeostasis, which probably accounts for the mild or asymptomatic forms of COVID-19 seen in most individuals.
T19 4903-4955 Sentence denotes IL-33 and cellular drivers of mild–moderate COVID-19
T20 4956-5391 Sentence denotes In susceptible individuals who develop symptomatic SARS-CoV-2 infection and COVID-19 pneumonia (eg, in the presence of individual cytokine or receptor polymorphisms), IL-33 might abnormally upregulate expression of its own receptor ST2 (also known as IL-1RL1) on Treg cells, resulting in increased expression of the canonical Th2 transcription factor GATA-binding factor 3 (GATA3), which impairs the suppressive function of Treg cells.
T21 5392-6466 Sentence denotes The dysregulation of GATA3+ Foxp3+ Treg cells might result in impaired immunological tolerance and increased secretion of type 2 cytokines, thus promoting autoinflammatory lung disease.16 TGFβ2, which is also increased in the bronchoalveolar lavage fluid of patients with COVID-19,11 might further enhance ST2 expression in innate lymphoid cells, and IL-33 is the key cytokine that drives these cells to differentiate into type 2 innate lymphoid cells (ILC2).17 ILC2 subsequently elicit lung inflammation by releasing large amounts of IL-9, which promotes their own survival and expands γδ T cells.18, 19 IL-9 is known to stimulate proliferation and expansion of Vγ9Vδ2+ T cells that have a predominantly effector memory phenotype and a combined Th1–Th17 cytokine response profile.19 When exposed to TGFβ, γδ T cells can also become an important source of IL-9.20 By acting in both autocrine and paracrine manners, IL-33-induced IL-9 might sustain a proinflammatory ILC2–γδT cell axis in the lungs of patients with COVID-19, thus initiating mild–moderate forms of pneumonia.
T22 6467-7107 Sentence denotes Both ILC2 and γδ T cells are centrally involved in lung homoeostasis and are rapidly activated in response to pathogens including viruses;19, 21 in COVID-19, IL-4 is upregulated at early stages and in milder forms of the disease,10 whereas IL-9 and activated γδ T cells are observed more frequently in mild-to-moderate disease,9, 22 and IFNγ and IL-17 progressively increase with disease severity.6 Vγ9Vδ2+ T cells from patients with COVID-19 have been found to express an effector memory phenotype three times more frequently than do conventional αβ T cells,23 thus suggesting that this T cell subset is selectively stimulated in COVID-19.
T23 7108-7432 Sentence denotes Because of significantly higher expression of the chemokine receptor CXCR3 compared with their αβ counterparts,24 γδ T cells might be rapidly recruited into inflamed lungs of patients with COVID-19 in response to the observed strong upregulation of the CXCR3 ligands CXCL9 and CXCL10 (figure 1 ).6, 9, 11, 15, 25, 26, 27, 28
T24 7433-7473 Sentence denotes Figure 1 T-cell polarisation in COVID-19
T25 7474-7647 Sentence denotes IL-33 released from virus-damaged cells might induce dysregulated GATA3+Foxp3+ Tregs and promote IL-2 production by dendritic cells, resulting in further expansion of Tregs.
T26 7648-7783 Sentence denotes IL-33 might also elicit differentiation of ILC2, with TGFβ enhancing ST2 expression on these cells and facilitating production of IL-9.
T27 7784-7956 Sentence denotes IL-9 in turn stimulates expansion of effector memory Vγ9Vδ2+ T cells with mixed Th1 and Th17 profiles that express CXCR3 and are recruited to the lungs by CXCL9 and CXCL10.
T28 7957-8140 Sentence denotes IL-9 possibly induces its own transcription factor PU.1 and thus act in an autocrine and paracrine manner (along with TGFβ) to drive proliferation and survival of ILC2 and γδ T cells.
T29 8141-8250 Sentence denotes Additional positive loops might be fed by IFNγ, which triggers production of CXCL9 and CXCL10 by macrophages.
T30 8251-8470 Sentence denotes In severe forms of COVID-19, IL-33, along with IL-2 and IL-7 released by dendritic cells, might further stimulate T-cell expansion through STAT5 and induce production of large amounts of GM-CSF by γδ and T helper cells.
T31 8471-8708 Sentence denotes At advanced stages of disease, aberrant activation of the MyD88-related NF-κB pathway and activation of the NLRP3 inflammasome might induce virus-exposed cells and infiltrating monocytes–macrophages to overproduce IL-1β, IL-23, and IL-6.
T32 8709-8911 Sentence denotes IL-1β, IL-23, IL-6, and IL-7 act on STAT3 and RORC, thus promoting differentiation of CCR2+ T cells that are recruited to the lungs by CCL2 and CCL8 into γδT17 and Th17 cells producing IL-17 and GM-CSF.
T33 8912-9001 Sentence denotes In turn, GM-CSF might further recruit and activate proinflammatory monocytes–macrophages.
T34 9002-9035 Sentence denotes CCR=C-C motif chemokine receptor.
T35 9036-9067 Sentence denotes CCL=C-C motif chemokine ligand.
T36 9068-9102 Sentence denotes CXCL=C-X-C motif chemokine ligand.
T37 9103-9133 Sentence denotes CXCR=C-X-C chemokine receptor.
T38 9134-9160 Sentence denotes Foxp=forkhead box protein.
T39 9161-9186 Sentence denotes GATA=GATA-binding factor.
T40 9187-9243 Sentence denotes GM-CSF=granulocyte-macrophage colony-stimulating factor.
T41 9244-9259 Sentence denotes IL=interleukin.
T42 9260-9293 Sentence denotes ILC2=type 2 innate lymphoid cell.
T43 9294-9349 Sentence denotes MyD88=myeloid differentiation primary response protein.
T44 9350-9379 Sentence denotes NF-κB=nuclear factor-kappa B.
T45 9380-9432 Sentence denotes NLRP=NACHT, LRR, and PYD domains-containing protein.
T46 9433-9464 Sentence denotes PU.1=transcription factor PU.1.
T47 9465-9497 Sentence denotes RORC=nuclear receptor ROR-gamma.
T48 9498-9515 Sentence denotes ST2=ST2 receptor.
T49 9516-9567 Sentence denotes STAT=signal transducer and transcription activator.
T50 9568-9599 Sentence denotes TGF=transforming growth factor.
T51 9600-9612 Sentence denotes Th=T-helper.
T52 9613-9637 Sentence denotes TLR=toll-like receptors.
T53 9638-9661 Sentence denotes Treg=regulatory T cell.
T54 9663-9726 Sentence denotes IL-33 induction of GM-CSF-expressing T cells in severe COVID-19
T55 9727-9848 Sentence denotes The cellular composition of lung infiltrates in patients with COVID-19 pneumonia changes with the progression of disease.
T56 9849-10408 Sentence denotes Infiltrates in patients with moderate pneumonia include mainly lymphoid and dendritic cells; whereas, severe forms of disease are characterised by massive infiltration of macrophages and neutrophils.15 In patients with COVID-19, expression of T-cell chemoattractants (eg, CXCL9, CXCL10) and their receptors (eg, CXCR3) precedes expression of monocyte and neutrophil chemoattractants (eg, CCL2, CCL3, CCL4, CCL7, CXCL8) and their corresponding receptors (eg, CCR1, CXCR2).15 The composition and phenotypes of lung macrophages also change with disease severity.
T57 10409-10947 Sentence denotes Resident alveolar (A-FABP4+) macrophages, which show scavenger and lipid metabolic functions typical of anti-inflammatory or resolving M2-like cells (eg, macrophage receptor MARCO, PPAR-γ, Apo-CI), predominate in mild and moderate forms, whereas CD14+ monocyte-derived macrophages (FCN1high) and chemoattractant (FCN1lowSPP-1+) macrophages, which show highly inflammatory M1-like profiles (eg, nuclear factor-kappa B [NF-κB], CCL2, CCL3), dominate tissue specimens from patients with severe forms of COVID-19 and who are critically ill.15
T58 10948-11276 Sentence denotes In the circulation of patients with COVID-19, amounts of proinflammatory CD14+CD16+ intermediate monocytes increase with disease severity, and upregulation of GM-CSF in CD4+ and CD8+ T cells might account for tissue recruitment and activation of neutrophils and monocyte-derived macrophages in most severe forms of the disease.5
T59 11277-12445 Sentence denotes Although described as Th1 cells, at least half of the GM-CSF-producing T cells observed in the circulation of patients with severe COVID-19 do not coexpress the canonical Th1 cytokine IFNγ.5 Lymphocytes from patients with COVID-19 appear to be functionally exhausted, producing lower amounts of IFNγ, IL-2, and tumour necrosis factor (TNF), and having decreased cytotoxic function.29 Many factors could possibly explain this lymphocyte dysfunction, in particular the upregulation of multiple coinhibitory receptors such as CD94, CD152 (cytotoxic T-lymphocyte-associated antigen 4), programmed cell death protein 1 (PD-1), and T-cell immunoglobulin mucin receptor 3 (TIM-3).29 However, suboptimal production of IFNγ, poor cytotoxic capabilities, a shorter lymphocyte lifespan, and lymphopenia might also be attributable to a scarcity in type I and III interferons (IFNα, IFNβ, and IFNλ), in the blood as well as in the lungs of patients with COVID-19.27 Interferons are more highly suppressed by SARS-CoV-2 than by SARS-CoV infection,27, 28 and this most likely accounts for the impaired antiviral responses and spontaneous apoptosis of dysfunctional lymphocytes.11, 30
T60 12446-12966 Sentence denotes Lymphocyte impairment in COVID-19 resembles the cytotoxic dysfunction of CD8+ cytotoxic T lymphocytes and natural killer cells observed in familial haemophagocytic lymphohistiocytosis, in which T cell dysfunction is the result of heterozygous mutations in genes affecting the expression of perforin or other proteins involved in the trafficking and docking of cytolytic granules,1 and in patients who are predisposed to MAS, in whom IL-6 overexpression can reduce perforin and granzyme B concentration inside granules.31
T61 12967-13356 Sentence denotes The inability to kill infected or activated antigen-presenting cells in patients with either MAS or COVID-19 could result in persistent interactions between T cells and antigen presenting cells, culminating in hyperproduction of cytokines as a result of overstimulation of both cell types.1 However, by contrast with COVID-19, IFNγ is not impaired in MAS, and is a major driver of disease.
T62 13357-13535 Sentence denotes In MAS, IFNγ-producing CD8+ T-cell populations are elevated in primary and secondary lymphoid organs, leading to IFNγ-driven macrophage hyperactivation and haemophagocytosis.1, 3
T63 13536-13766 Sentence denotes The effects of IFNγ deficiency have been investigated in an experimental model of haemophagocytic lymphohistiocytosis, which develops when perforin deficient (Prf1−/−) mice are infected with the lymphocytic choriomeningitis virus.
T64 13767-13967 Sentence denotes Surprisingly, mice lacking both IFNγ and perforin (IFNγ−/−Prf1−/−) still develop a severe MAS-like disease that requires the IL-33–ST2 axis and is downstream mediated by GM-CSF-producing CD8+ T cells.
T65 13968-14301 Sentence denotes The inflammatory burden in infected IFNγ−/−Prf1−/− mice is even higher than in Prf1−/− mice, being characterised by a 10–15 times increase in neutrophils and stronger upregulation of IL-1β and IL-6.32 The same interplay between IL-33 and GM-CSF might occur in patients with COVID-19, which would initiate the cytokine storm syndrome.
T66 14302-14426 Sentence denotes Thus, severe forms of COVID-19 might represent atypical MAS or MAS-like reactions with incorporated interferon deficiencies.
T67 14428-14474 Sentence denotes Cellular expansion in severe–critical COVID-19
T68 14475-14715 Sentence denotes Failure of lymphocytes to adequately respond to viral antigens and proapoptotic signals might induce dendritic cells to produce large amounts of the lymphocyte growth factors IL-7 and IL-2, thereby stimulating T-cell survival and expansion.
T69 14716-15346 Sentence denotes High concentrations of IL-2 and IL-7 in serum are characteristic of severe COVID-19 cases.6, 9 However, IL-2 and IL-7 might amplify ILC2 survival and differentiation induced by IL-33,33 expand γδ T cells, which produce IL-17 through the signal transducer and activator of transcription (STAT)3,34 and enhance IL-33-induced pathologic expansion of T cells expressing GM-CSF through STAT5.35, 36 Patients infected with SARS-CoV-2 show an increase in circulating CD4+ γδ T cells that overexpress the IL-2 receptor CD25 but not PD-1, suggesting that these cells are not exhausted, but are specifically activated in response to IL-2.22
T70 15347-16029 Sentence denotes IL-7 enables γδ T cells to fully differentiate into γδT17 cells34 that coproduce IL-17F along with IL-17A, and rapidly migrate into inflamed tissues in response to CCR2 and CCR5 ligands such as CCL2 and CCL8.37, 38 As shown for murine γδT17 cells, human Vδ2+ T cells that co-express CCR2 and CCR5 also express the IL-7 receptor and show a Th17-like phenotype (CCR6+CD161+IL-23R+).39 Transcriptional analyses of respiratory cell populations in response to SARS-CoV-2 infection reveal strong upregulation of CCL8, CCL2, CXCL9, CXCL10 and their respective receptors,11, 15, 27 and global upregulation of IL-17 and IL-17F-related pathways,26 including the CCR6 ligand CCL20 and IL-23.27
T71 16030-16599 Sentence denotes IL-23 and IL-1β are required for GM-CSF production by γδT17 cells and conventional αβ Th17 cells.40, 41 In models of autoimmunity in which GM-CSF is a key pathogenic molecule, such as experimental autoimmune encephalomyelitis, γδ T cells have been identified as the major source of GM-CSF.42 Whereas conventional αβ Th17 cells evolve to produce IFNγ during the development of the disease, γδT17 cells are less likely to produce IFNγ and will more likely evolve to produce GM-CSF.42 As for γδT17, recruitment of IL-23-driven, GM-CSF-producing Th17 cells requires CCR2.43
T72 16600-16836 Sentence denotes By promptly releasing multiple cytokines such as IL-9, IL-17, IL-17F, TNF, IFNγ, and GM-CSF, γδT17 might be instrumental in recruiting neutrophils and proinflammatory monocytes into the capillaries and alveoli of patients with COVID-19.
T73 16837-17104 Sentence denotes Moreover, activation of γδ T cells might be important in the cytokine-driven induction of procoagulant tissue factor in endothelial cells,44 thus also having a potential role in vascular manifestations and pulmonary thromboses associated with COVID-19 pneumonia.2, 29
T74 17105-17732 Sentence denotes Cytotoxicity against virus-infected alveolar epithelial cells by γδ T cells has been shown for influenza virus45 and might involve atypical pathways alternative to granzyme B and perforin, which are more commonly used by CD8+ T cells and natural killer cells and could be impaired in COVID-19 and MAS.1, 29, 31 Specifically, γδ T cells might exert cytotoxic effects through the TNF-related apoptosis-inducing ligand, Fas ligand, and granzyme K,39, 45 which are all overexpressed in the lungs of patients with COVID-19,11, 15 and might therefore explain how γδ T cells cause diffuse damage to the alveolar epithelium (figure 1).
T75 17734-17790 Sentence denotes Suppression of antiviral responses and hyperinflammation
T76 17791-18169 Sentence denotes Advanced stages of COVID-19 are characterised by high circulating and pulmonary concentrations of IL-1α, IL-1β, and IL-1 receptor antagonist (IL-1RA).6, 15, 25 The increased production of these molecules probably relates to high viral loads resulting in increased viroporins and subsequent activation of the NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome.
T77 18170-18554 Sentence denotes The strong expression of IL-1α, IL-1β, and IL-1RA is also due to monocyte activation and intense lung infiltration of monocyte-derived macrophages at later stages, as suggested by an abundance of CD14+IL-1β+ monocytes in the circulation of patients with COVID-19 in the early stages of recovery.46 Active IL-1β is produced following NLRP3 assembly and consequent caspase-1 activation.
T78 18555-18785 Sentence denotes By modulating ion fluxes across host cell membranes, viroporins (in particular the ORF3a protein) have been shown to activate NLRP3 during SARS-CoV infection, and a similar mechanism might be at play during SARS-CoV-2 infection.47
T79 18786-20094 Sentence denotes An imbalance in signalling from toll-like receptor (TLR) pathways, with the myeloid differentiation primary response protein (MyD88) pathway predominating over the TIR domain-containing adapter molecule 1 (TICAM-1, also known as TRIF) pathways, might further increase NLRP3 activation.48 Signalling downstream of IL-1 family receptors, including the IL-33 receptor ST2, and downstream of membrane TLRs, can activate MyD88 and elicit inflammation; whereas TRIF-mediated pathways downstream of endosomal TLRs would be expected to mount antiviral interferon responses and protect against coronaviruses.48, 49 Although coronaviruses are single-stranded RNA viruses that are predicted to bind directly to endosomal TLR7 and TLR8, and indirectly to TLR3 (using double-stranded RNA replication intermediates), aberrant inflammation induced by coronaviruses might instead involve membrane-expressed TLR2, as suggested by virus spike protein interactions with heparan sulphate-enriched regions of TLR2 in studies of the mouse hepatitis coronavirus.50 A predominance of MyD88 signalling over TRIF signalling would lead virus-exposed cells to produce high amounts of IL-1β, and NF-κB-induced cytokines and chemokines (eg, TNF, IL-8, IL-6, IL-12p40, IL-23, CCL2) rather than interferons, IL-12p35 and IL-12p70.30, 49, 50
T80 20095-20855 Sentence denotes High concentrations of MyD88-related cytokines and reduced expression of TRIF-related cytokines characterise the cytokine milieu observed in the lungs of patients with severe and life-threatening COVID-19.15, 27, 28 Such an altered cytokine environment would polarise the immune response towards detrimental (Th17-sustained and GM-CSF-induced) hyperinflammation40, 41 caused by monocyte-derived macrophages and neutrophils, in place of protective (Th1-sustained and IFN-induced) antiviral responses exerted by cytotoxic T lymphocytes, natural killer cells, and B cells.29, 30 Altogether, coronaviruses seem to deceive and escape the immune system by eliciting a response that is generally more appropriate for extracellular rather than intracellular pathogens.
T81 20857-20915 Sentence denotes IL-33 and pathway synergisms in critical systemic COVID-19
T82 20916-21431 Sentence denotes In addition to NLRP3 stimulation and IL-1 release,47 substantial amounts of viroporins in patients with life-threatening COVID-19 might also account for extensive injury of alveolar epithelial cells and overproduction of IL-33.51 IL-33, IL-1α, and GM-CSF also stimulate each other's release by alveolar type 2 pneumocytes.52, 53 Accordingly, diffuse alveolar damage with alveolar denudation and reactive type 2 pneumocyte hyperplasia are histological hallmarks of COVID-19 with acute respiratory distress syndrome.4
T83 21432-22733 Sentence denotes Feedforward loops might also engage mast cells, macrophages, endothelial cells, T cells, and neutrophils.40, 54 Although whether mast cells and macrophages produce IL-33 is still up for debate,51 it is well established that mast cells, infiltrating neutrophils, and cytotoxic T lymphocytes secrete serine proteases (eg, tryptase, cathepsin G, elastase, granzymes) that cleave IL-33 released from damaged epithelial and endothelial barriers into a mature form of IL-33 that is 10–30 times more active.51 IL-33 amplifies lung inflammation by inducing various proinflammatory cytokines (eg, GM-CSF, IL-1β, IL-6, TNF, granulocyte colony-stimulating factor [G-CSF]), chemokines (eg, CXCL1, CXCL2, CXCL6, CXCL8, CCL2, CCL20), and adhesion molecules (eg, E-selectin, ICAM1, VCAM1) in several target cells.32, 54, 55, 56, 57 Conversely, by inhibiting type 1 interferons and IL-12p35, IL-33 might contribute to impaired antiviral cytotoxic responses.58 In models of MAS-like disease, IL-33 is a crucial contributor to the weight loss and hyperferritinaemia related to systemic hyperinflammation, and to the expansion of GM-CSF-producing CD8+ T cells, upregulation of IL-1β and IL-6, and tissue neutrophilia.32 These features are the same as key characteristics seen in patients with critical COVID-19.5, 15, 26
T84 22734-23103 Sentence denotes IL-33 has also been implicated in the formation of neutrophil extracellular traps during virus-induced asthma exacerbation.58 Similarly, neutrophil priming with GM-CSF might promote the production of neutrophil extracellular traps.59 By releasing neutrophil elastase and other proteinases, neutrophil extracellular traps could in turn cleave and further activate IL-33.
T85 23104-23430 Sentence denotes These pathways might be relevant in patients with critical COVID-19, since neutrophilia and the neutrophil-to-lymphocyte ratio are associated with poor prognosis, and high concentrations of neutrophil extracellular traps have been detected in patients with COVID-19 admitted to hospital and receiving mechanical ventilation.60
T86 23431-24367 Sentence denotes Neutrophil extracellular traps might propagate inflammation and microvascular thrombosis in patients with COVID-19 and severe acute respiratory distress syndrome.60 Along with IL-33, IL-1, TNF, and other cytokines, neutrophil extracellular traps might increase endothelial permeability and induce a procoagulant phenotype in endothelial tissues by inducing expression of tissue factor,61, 62, 63 thus representing a possible link between hyperinflammation and hypercoagulability that could account for D-dimer elevation, pulmonary thrombosis, and microvascular manifestations affecting the heart, kidneys, and small bowel seen in patients with critical COVID-19.64, 65 Endothelialitis and endothelial dysfunction would also account for predominant exudative-phase diffuse alveolar damage characterised by hyaline membranes and fibrin deposits typically observed in patients with COVID-19 and severe acute respiratory distress syndrome.4
T87 24368-24695 Sentence denotes IL-33 has also been shown to stimulate expression of IL-1β, IL-6, CCL2, CXCL2, and G-CSF by adipocytes.57 Elevated circulating concentrations of soluble ST2 (measured more often than IL-33 because of its higher concentration and stability) are associated with obesity, diabetes, hypertension, and acute cardiovascular diseases.
T88 24696-25291 Sentence denotes High soluble ST2 concentrations also predict worse outcomes and are associated with extension of heart damage, heart failure, increased cardiovascular death, and all-cause mortality.54 Notably, diabetes, hypertension, and cardiovascular diseases are common comorbidities in patients with COVID-19, and obesity has been independently associated with increased severity and mortality among younger patients with COVID-19.66 Circulating concentrations of soluble ST2 correlate with the extent of tissue damage, and might represent an indicator in plasma of IL-33 release and bioactivity in tissues.
T89 25292-25639 Sentence denotes Production of soluble ST2 might be reduced by anti-ST2 treatment, and such reduction would modulate T-cell polarisation by decreasing pathogenic Th1 and Th17 cells, and increasing IL-10-producing Treg cells.67 Future research should focus on whether soluble ST2 concentrations in plasma have prognostic value in patients with COVID-19 (figure 2 ).
T90 25640-25706 Sentence denotes Figure 2 IL-33 might orchestrate all pathogenic phases of COVID-19
T91 25707-25816 Sentence denotes IL-33 might induce numerous cytokines and chemokines as well as its own receptor, ST2, in various cell types.
T92 25817-26058 Sentence denotes In asymptomatic or paucisymptomatic patients, IL-33 might expand anti-inflammatory Foxp3+ Treg cells or induce IL-4 production by GATA3+Foxp3+ Tregs and ILC2, thus stimulating mast cells, which might account for minor, allergy-like symptoms.
T93 26059-26253 Sentence denotes In individuals with mild-to-moderate disease, IL-33 (along with TGFβ) might induce ILC2 to release large amounts of IL-9, driving local expansion of effector memory Vγ9Vδ2+ T cells in the lungs.
T94 26254-26409 Sentence denotes In moderate–to-severe pneumonia, IL-33 combined with IL-2 and IL-7 from dendritic cells might further expand ILC2, γδT cells, and GM-CSF-producing T cells.
T95 26410-26533 Sentence denotes In severe–critical COVID-19, IL-33, GM-CSF, and IL-1 might stimulate each other's release by acting on multiple cell types.
T96 26534-26760 Sentence denotes IL-33 induction of cytokines, chemokines, adhesion molecules, tissue factor, and neutrophil extracellular traps might contribute to endothelialitis, thrombosis, and extrapulmonary involvement in patients with MAS-like disease.
T97 26761-27040 Sentence denotes Neutrophil extracellular traps and mast cell degranulation could provoke protease-mediated cleavage of IL-33 into a 10–30 times more potent form, and IL-33-induced release of its soluble receptor ST2 might further polarise T cells and contribute to cardiovascular manifestations.
T98 27041-27305 Sentence denotes In patients who survive, IL-33 might drive the post-acute fibrotic phase thorugh induction of IL-13 and TGFβ in M2-differentiated macrophages and ILC2, thereby stimulating myofibroblasts and eliciting the epithelial–to–mesenchymal transition of type 2 pneumocytes.
T99 27306-27469 Sentence denotes Molecules inside brackets are part of self-amplifying proinflammatory loops fed by IL-33 and outside brackets indicate different factors possibly induced by IL-33.
T100 27470-27577 Sentence denotes Question mark indicates the uncertainty of whether mast cells produce IL-33. bFGF=fibroblast growth factor.
T101 27578-27609 Sentence denotes CCL=C-C motif chemokine ligand.
T102 27610-27647 Sentence denotes CTGF=connective tissue growth factor.
T103 27648-27682 Sentence denotes CXCL=C-X-C motif chemokine ligand.
T104 27683-27762 Sentence denotes DIC=(systemic vascular thromboses mimicking) diffuse intravascular coagulation.
T105 27763-27801 Sentence denotes EMT=epithelial-mesenchymal transition.
T106 27802-27828 Sentence denotes Foxp=forkhead box protein.
T107 27829-27854 Sentence denotes GATA=GATA-binding factor.
T108 27855-27899 Sentence denotes G-CSF=granulocyte colony-stimulating factor.
T109 27900-27956 Sentence denotes GM-CSF=granulocyte-macrophage colony-stimulating factor.
T110 27957-27981 Sentence denotes ICU=intensive care unit.
T111 27982-27997 Sentence denotes IFN=interferon.
T112 27998-28013 Sentence denotes IL=interleukin.
T113 28014-28047 Sentence denotes ILC2=type 2 innate lymphoid cell.
T114 28048-28083 Sentence denotes MAS=macrophage activation syndrome.
T115 28084-28111 Sentence denotes MOF=multiple organ failure.
T116 28112-28146 Sentence denotes NET=neutrophil extracellular trap.
T117 28147-28183 Sentence denotes PDGF=platelet-derived growth factor.
T118 28184-28281 Sentence denotes P/F ratio=arterial oxygen partial pressure to fractional inspired oxygen ratio. sST2=soluble ST2.
T119 28282-28299 Sentence denotes ST2=ST2 receptor.
T120 28300-28331 Sentence denotes TGF=transforming growth factor.
T121 28332-28353 Sentence denotes TF-1=tissue factor-1.
T122 28354-28381 Sentence denotes TNF=tumour necrosis factor.
T123 28382-28426 Sentence denotes TRAIL=TNF-related apoptosis-inducing ligand.
T124 28427-28450 Sentence denotes Treg=regulatory T cell.
T125 28452-28521 Sentence denotes Similarities between COVID-19, Kawasaki disease, and Behçet's disease
T126 28522-28929 Sentence denotes Parallels between COVID-19 and rheumatic disorders can be made by referring to discrete autoinflammatory syndromes that share symptoms with COVID-19 such as fever, frequent conjunctivitis, and—most remarkably—vasculitic manifestations with neutrophilia, thrombosis, and aneurysmal dilations, involving coronary vessels (eg, Kawasaki disease in infants) or pulmonary vessels (eg, Behçet's disease in adults).
T127 28930-29861 Sentence denotes Case series of children infected with SARS-CoV-2 who develop Kawasaki-like disease with MAS features have been described.68 GM-CSF produced by cardiac fibroblasts is key in disease progression in mouse models of Kawasaki disease, and significantly increased soluble ST2, E-selectin, CXCL10, IL-17F, and in some cases IL-9, have been reported in the circulation of patients with acute Kawasaki disease compared with other children who are febrile.69, 70, 71 Similarly, Behçet's disease has been associated with high concentrations of both soluble ST2 and IL-33, as well as increased CXCL10 and CCL2, Vγ9Vδ2 T-cell expansion, IL-17F gene polymorphisms, and intense recruitment of T cells producing IL-9 and IL-17 to the lungs.72, 73, 74, 75, 76 Some patients with either Behçet's disease77 or COVID-1978 also show positivity for antiphospholipid antibodies, which might further contribute to the coagulopathy seen in both conditions.
T128 29863-29920 Sentence denotes IL-33 induction of pulmonary fibrosis in chronic COVID-19
T129 29921-30122 Sentence denotes Lung alveolar inflammation in COVID-19 is accompanied by loose interstitial fibrosis and can result in widespread fibrotic changes.79 IL-33 could also be important at these later stages of the disease.
T130 30123-30510 Sentence denotes In a bleomycin-induced pulmonary fibrosis mouse model, the IL-33–ST2 axis is required to induce alternatively activated M2 macrophages and ILC2 to release key profibrotic cytokines.80 IL-33-activated mast cells might also play a role in organ fibrosis.81 Most remarkably, IL-33 has been shown to induce epithelial-to-mesechymal transition of type 2 pneumocytes through TGFβ signalling.82
T131 30511-31055 Sentence denotes IL-33 concentrations are elevated in patients with systemic sclerosis and correlate with the severity of pulmonary fibrosis, and patients with idiopathic pulmonary fibrosis show increased serum concentrations of soluble ST2 when the disease is exacerbated.82 IL-33 can induce cytokines (eg, TGFβ, IL-13) and chemokines (eg, CCL2, CXCL6) involved in pulmonary fibrosis, which are also increased in patients infected with SARS-CoV-2,6, 9, 11, 15, 26 thus suggesting additional roles for IL-33 in driving the post-acute fibrotic phase of COVID-19.
T132 31056-31355 Sentence denotes Growth factors such as vascular endothelial growth factor, platelet-derived growth factor, and fibroblast growth factor are all involved in fibrotic processes and are overexpressed in patients with COVID-19,9 and γδ T cells exposed to TGFβ might produce connective tissue growth factor (figure 2).83
T133 31357-31381 Sentence denotes Implications for therapy
T134 31382-32090 Sentence denotes Although more conclusive results are awaited from randomised controlled trials, encouraging preliminary results have been reported for the successful management of severe and critical COVID-19 by therapeutic modulation of IL-1α and IL-1β with recombinant IL-1RA (anakinra)84, 85 and by blocking GM-CSF using monoclonal antibodies (mavrilimumab, lenzilumab).86, 87 Although some studies have shown that IL-6 peaks at advanced stages of COVID-19 and is associated with disease severity,2, 10, 15 other studies have reported conflicting data on IL-6 and IL-6 receptor expression in patients,9, 11 and the results with anti-IL-6 receptor antibodies (eg, tocilizumab, sarilumab) have been controversial.88, 89, 90
T135 32091-32224 Sentence denotes Targeting IL-33 (eg, by using anti-ST2 antibodies such as astegolimab), could be the key for controlling excessive lung inflammation.
T136 32225-33517 Sentence denotes In a mouse model of influenza virus-induced asthma exacerbation,58 administration of an anti-ST2 antibody significantly reduced airway hyper-responsiveness and bodyweight loss, lowered inflammatory cell numbers in the lungs, and eliminated neutrophil extracellular traps in the airway lumen; moreover, anti-ST2 treatment restored lung expression of IFNβ, IL-12p35, and IL-12p70, and reduced viral load.58 There are several ongoing phase 2 trials using anti-ST2 therapy for inflammatory lung diseases such as chronic obstructive pulmonary disease and asthma.12 In the IFNγ-deficient mouse model of atypical MAS, blocking ST2 provided significant protection against weight loss, increased survival, reduced serum ferritin and soluble CD25 concentrations, and lowered CD8+ T-cell frequencies and neutrophilia.32 By contrast, individually blocking IL-6, IL-1β, or GM-CSF did not provide major protection against disease, suggesting that dampening IL-33–ST2 signalling, rather than individual downstream effector cytokines, might be more effective in treating either canonical MAS or atypical MAS-like diseases,32 such as COVID-19.2 A study evaluating the safety and efficacy of astegolimab (MSTT1041A) in severe COVID-19 pneumonia is recruiting participants (NCT04386616; EudraCT 2020-002713-17).
T137 33518-33738 Sentence denotes The anti-IL-33 monoclonal antibody, MEDI3506, has also been included among possible therapies for the treatment of hospitalised patients with COVID-19 and is currently being tested in a phase 2 adaptive platform study.91
T138 33739-33945 Sentence denotes Additional important cell targets to focus on include ILC2, IL-17-producing and GM-CSF-producing γδT17 cells, proinflammatory monocytes–macrophages, extracellular trap-producing neutrophils, and mast cells.
T139 33946-34331 Sentence denotes Different strategies could be set up to control aberrant activation of these cells, for instance by targeting IL-9 (MEDI-528), Vγ9Vδ2 T-cell activation (pentoxifylline),74 IL-17A, IL-17F, and IL-17E (bimekizumab, brodalumab),92 and cytokine balance (using colchicine,93 NLRP3 inhibitors,94 TLR2 inhibitors,95 JAK2 inhibitors,96 apremilast,97 mast cells stabilisers,55 and vitamin D).98
T140 34332-34599 Sentence denotes Acting more directly on the T-cell homing by using anti-CCR5 (leronlimab),99 anti-CCR2 (prozalizumab), CCR2 and CCR5 inhibitors (BMS-813160), anti-CCL2 (carlumab), or anti-CCL8 antibodies, might be another crucial strategy in the management of patients with COVID-19.
T141 34600-34801 Sentence denotes Additionally, anti-CCR1 (AZD4818) and anti-CXCR2 (AZD5069) antibodies, which selectively act on recruitment of monocytes and neutrophils, might be considered for patients at advanced stages of disease.
T142 34802-35207 Sentence denotes In patients with post-acute respiratory distress syndrome, diverse antifibrotic agents acting on TGFβ (fresolimumab, pirfenidone), IL-13 (lebrikizumab, dupilumab),100 connective tissue growth factor (pamrevlumab), fibroblast growth factor, platelet-derived growth factor, and vascular endothelial growth factor signalling (nintedanib),79 might all represent viable therapeutic options (figure 3 , table ).
T143 35208-35276 Sentence denotes Figure 3 Inflammatory patterns in COVID-19 at various disease stages
T144 35277-35533 Sentence denotes Cytokine interplay between IL-33, GM-CSF, IL-1α, and IL-1β, and key cytokines, chemokines, and receptors, the composition of lung inflammatory infiltrates, cell phenotypes involved, and possible therapeutic options according to different stages of disease.
T145 35534-35567 Sentence denotes CCR=C-C motif chemokine receptor.
T146 35568-35599 Sentence denotes CCL=C-C motif chemokine ligand.
T147 35600-35627 Sentence denotes CXCL=C-X-C motif chemokine.
T148 35628-35664 Sentence denotes CXCR=C-X-C motif chemokine receptor.
T149 35665-35697 Sentence denotes FABP=fatty acid-binding protein.
T150 35698-35710 Sentence denotes FCN=ficolin.
T151 35711-35741 Sentence denotes FGF=fibroblast growth factors.
T152 35742-35767 Sentence denotes GATA=GATA-binding factor.
T153 35768-35837 Sentence denotes GM-CSF=granulocyte-macrophage colony-stimulating factor. i=inhibitor.
T154 35838-35853 Sentence denotes IFN=interferon.
T155 35854-35869 Sentence denotes IL=interleukin.
T156 35870-35903 Sentence denotes ILC2=type 2 innate lymphoid cell.
T157 35904-35921 Sentence denotes JAK=Janus kinase.
T158 35922-35974 Sentence denotes NLRP=NACHT, LRR, and PYD domains-containing protein.
T159 35975-36011 Sentence denotes PDGF=platelet-derived growth factor.
T160 36012-36099 Sentence denotes PDGF-Ri=platelet-derived growth factor receptor inhibitor. rIL=recombinant interleukin.
T161 36100-36147 Sentence denotes SPP=secreted phosphoprotein. sST2= soluble ST2.
T162 36148-36165 Sentence denotes ST2=ST2 receptor.
T163 36166-36197 Sentence denotes TGF=transforming growth factor.
T164 36198-36210 Sentence denotes Th=T-helper.
T165 36211-36234 Sentence denotes TLR=toll-like receptor.
T166 36235-36258 Sentence denotes Treg=regulatory T cell.
T167 36259-36299 Sentence denotes VEGF=vascular endothelial growth factor.
T168 36300-36364 Sentence denotes Table Advantages and disadvantages of various drugs for COVID-19
T169 36365-36420 Sentence denotes Molecular targets Cell targets Advantages Disadvantages
T170 36421-37590 Sentence denotes Anti-ST2 (eg, astegolimab), anti-IL-33 (eg, MEDI-3506), small-molecule ST2 inhibitors IL-33-ST2 axis, soluble ST2 GATA3+ regulatory T cells, ILC2, type 2 pneumocytes, IL-2 and IL-7-producing dendritic cells, IL-9 and IL-7-driven γδT17 cells, GM-CSF-producing T cells, neutrophils, endothelial cells, mast cells, and M2 macrophages Effective against virus-induced exacerbations of asthma, might restore antiviral interferon responses; effective in haemophagocytic lymphohistiocytosis and MAS-like models incorporating interferon deficiencies (resembling severe–critical COVID-19); might be effective at all stages of COVID-19; and has potential against obesity-related severe COVID-19 Complexity of IL-33 biology—eg, nuclear versus extracellular cytokine, full-length versus cleaved form, membrane versus soluble receptor (targeting ST2 over IL-33 seems safer); atheroprotective and cardioprotective roles hypothesised for IL-33; unclear whether suppression of proinflammatory Th1 and Th17 cells by anti-ST2 favours Th2 responses along with regulatory T cell expansion; however, inhibition of ILC2, M2 and type 2 pneumocytes should overall result in antifibrotic effects
T171 37591-37949 Sentence denotes Anti-GM-CSF (eg, mavrilimumab, gimsilumab, lenzilumab, otilimab) GM-CSF Type 2 pneumocytes, monocytes, macrophages, neutrophils, endothelial cells Encouraging preliminary data in severe-to-critical COVID-19 and good safety Might be less effective at earlier stages; possibly interferes with alveolar macrophage homoeostasis and alveolar surfactant production
T172 37950-38384 Sentence denotes Recombinant IL-1RA (eg, anakinra), anti-IL-1β (eg, canakinumab), recombinant IL-37 IL-1α and IL-1β, or IL-1β Type-2 pneumocytes, GM-CSF-producing γδT and Th17 cells, monocytes, macrophages, neutrophils, endothelial cells, adipocytes Encouraging preliminary data in severe–critical COVID-19; potential against obesity-related severe forms of COVID-19; good safety (short half-life of anakinra) Might be less effective at earlier stages
T173 38385-38700 Sentence denotes Recombinant IL-36RA or IL-38 IL-36 cytokines T cells, mast cells, neutrophils, monocytes, macrophages, endothelial cells, fibroblasts IL-36α promotes influenza virus-induced lung injury and mortality IL-36β supports antiviral interferon responses; IL-36γ supports alveolar macrophage survival during viral infection
T174 38701-39200 Sentence denotes Anti-IL-6 receptor (eg, tocilizumab, sarilumab), anti-IL-6 (eg, clazakizumab, siltuximab) IL-6 Natural killer cells, T cells, B cells, endothelial cells Might help restore suppressed natural killer cell functions and oppose acute respiratory distress syndrome development IL-6 might have homoeostatic roles and induce SOCS3, IL-4Rα and CD163; conflicting preliminary results in severe–critical COVID-19; might favour bacterial, viral, and opportunistic infections (long half-life of IL-6 inhibitors)
T175 39201-39740 Sentence denotes Anti-IFNγ (eg, emapalumab) IFNγ Macrophages, dendritic cells, B cells, T cells, endothelial cells Might inhibit macrophage hyperactivation and induction of CXCL9 and CXCL10; might partly inhibit pathogenicity of effector T cells coexpressing GM-CSF and IFNγ Exogenous IFNγ inhibited the expression of GM-CSF by CD8+ T cells in haemophagocytic lymphohistiocytosis and MAS-like models with IFNγ deficiency; and anti-IFNγ might dampen protective antiviral cytotoxic T lymphocytes and B-cell responses orchestrated by interferons and Th1 cells
T176 39741-40067 Sentence denotes Antimalarials (eg, chloroquine, hydroxychloroquine) Endosomal toll-like receptors Dendritic cells, monocytes, macrophages, neutrophils, B cells, pneumocytes Might inhibit virus entry in vitro Possibly dampen endosomal toll-like receptor-induced, TRIF-mediated, protective, type 1 interferon signalling; possible cardiotoxicity
T177 40068-40603 Sentence denotes Type 3 interferons (eg, peg-interferon lambda-1, or recombinant IL-29) Anti-viral immune responses Pneumocytes (tissue-barrier epithelial cells), dendritic cells, macrophages, neutrophils IFNλ might overcome suppression of interferons and stimulate antiviral immune responses without detrimental hyperinflammation (restricted expression pattern of IFNλ receptor 1); less inflammatory side-effects than IFNα in patients with hepatitis C virus and in influenza-infected mice Knowledge of interferon lambda biology in humans is incomplete
T178 40604-40981 Sentence denotes Heparins (and small molecule toll-like receptor 2 inhibitors) Virus interaction with heparan sulphate on cell membranes Virus-susceptible host cells Possibly block coronavirus-induced, toll-like receptor 2-mediated, TNF and IL-6 production; might inhibit virus entry; and have antithrombotic effects Effective dose and best route of administration are unclear; risk of bleeding
T179 40982-41333 Sentence denotes Anti-IL-4Rα (eg, dupilumab), anti-IL-13 (eg, lebrikizumab) IL-4 and IL-13, or IL-13 M2 macrophages, ILC2, Th2 cells, mast cells, eosinophils, B cells, myofibroblasts Might inhibit virus-induced asthma exacerbations; and have a potential benefit in pulmonary fibrosis Possible exacerbation of Th17 responses and neutrophilia in severe–critical COVID-19
T180 41334-41691 Sentence denotes Anti-IL-9 (eg, MEDI-528) IL-9 ILC2, γδT17 cells, effector memory T cells, neutrophils, mast cells, M2 macrophages Might inhibit expansion of lymphoid cells, mast cell activation, and neutrophil recruitment in COVID-19 pneumonia; and might inhibit production of TGFβ and pulmonary fibrosis Might favour proinflammatory activation of monocytes and macrophages
T181 41692-42094 Sentence denotes Anti-IL-17A and anti-IL-17F (eg, bimekizumab), anti-IL-17RA (eg, brodalumab) IL-17A, IL-17F, IL-17E (or IL-25) Neutrophils, monocytes, macrophages, mast cells, endothelial cells, fibroblasts, ILC2 Might inhibit neutrophil recruitment and detrimental inflammation in severe COVID-19; and by acting on IL-25, brodalumab could also inhibit ILC2 differentiation Might favour fungal and bacterial infections
T182 42095-42473 Sentence denotes Selective JAK2 inhibitors (eg, fedratinib) IL-23, IL-6 γδT17 cells, Th17, GM-CSF-producing T cells, mast cells, neutrophils Possibly inhibit inflammation in severe COVID-19 and do not interfere with JAK1-dependent interferon signalling Do not interfere with IL-9, IL-2, and IL-7-mediated expansion of effector T cells; might favour bacterial, viral, and opportunistic infections
T183 42474-43006 Sentence denotes Anti-CCR2 (eg, prozalizumab), anti-CCR5 (eg, leronlimab), dual CCR2 and CCR5-inhibitors (eg, BMS-813160) CCR2 or CCR5, or both γδT17 cells, GM-CSF-producing T cells, monocytes, macrophages Might inhibit homing of mononuclear cells; encouraging data have been shown for leronlimab on restoration of immune functions in COVID-19 and clinical improvement; good safety Redundancy and complexity of the chemokine receptor system; several compounds targeting CCR2 or CCR5 did not show clinical efficacy as presumed from preclinical models
T184 43007-43237 Sentence denotes Anti-CCL2 (eg, carlumab), anti-CCL8 CCL2 or CCL8 γδT17 cells, T cells, monocytes, macrophages, neutrophils, fibroblasts Possibly act on different stages of COVID-19 Use of carlumab was unsuccessful in idiopathic pulmonary fibrosis
T185 43238-43490 Sentence denotes Anti-CCR1 (eg, AZD4818), anti-CXCR2 (eg, AZD5069) CCR1 or CXCR2 Monocytes, macrophages, neutrophils Possibly inhibit tissue recruitment of monocytes and neutrophils Use of these drugs was unsuccessful in chronic obstructive pulmonary disease and asthma
T186 43491-43796 Sentence denotes Colchicine Tubulin (cytoskeleton) Monocytes, macrophages, pneumocytes, neutrophils, endothelial cells, platelets Might inhibit NLRP3 assembly, neutrophil recruitment, and platelet aggregation; has antiviral properties Use of colchicine was unsuccessful in idiopathic pulmonary fibrosis; frequent diarrhoea
T187 43797-44110 Sentence denotes NLRP3 inflammasome inhibitors (eg, dapansutrile, CP-456773) NLRP3 Macrophages and other cells Shown to inhibit caspase-1, thereby preventing activation of IL-1β and IL-18; effective in murine models of pulmonary inflammation; and have a potential benefit in heart failure Might be less effective at earlier stages
T188 44111-44549 Sentence denotes Non-selective phosphodiesterase inhibitors (eg, pentoxifylline) Phosphodiesterases (adenosine receptor A2A-dependent mechanisms) γδ T cells, alveolar macrophages, mast cells, neutrophils, endothelial cells, platelets Might inhibit proinflammatory Vγ9Vδ2 T cells and TNF release; anti-inflammatory effects in experimental acute lung injury; haemorheological and antithrombotic properties; broad-spectrum antiviral activity Risk of bleeding
T189 44550-44898 Sentence denotes Phosphodiesterase-4 inhibitors (eg, apremilast) Phosphodiesterase-4 (enhanced by adenosine receptor A2A agonists) Monocytes, macrophages, dendritic cells, T cells, fibroblasts Possibly inhibit production of CXCL10, interferon gamma, IL-23, TNF, and leucocyte infiltration; ameliorate pulmonary inflammation in experimental models Frequent diarrhoea
T190 44899-45146 Sentence denotes Mast cell stabilisers (eg, sodium cromoglycate, ketotifen) Ion (calcium) channels, histamine receptor H1 Mast cells Might act on several symptomatic and pathogenic aspects of COVID-19 Might cause sedation, possibly favouring respiratory depression
T191 45147-45548 Sentence denotes Vitamin D Vitamin D response elements Regulatory T cells, effector T cells, dendritic cells, adipocytes, mast cells Possibly shifts the T cell balance in favour of regulatory T cells rather than Th9 and Th17; might inhibit Vγ9Vδ2 T cells and adipocyte release of CCL2, and stabilise mast cells Appropriate dosage for use as an immunomodulant is not defined; potential toxicity linked to hypercalcaemia
T192 45549-45859 Sentence denotes Anti-(pan)TGFβ (eg, fresolimumab) TGFβ(2) ILC2, IL-9, and IL-17- producing T cells, M2 macrophages, fibroblasts, pneumocytes Might act on different stages of COVID-19; might inhibit ST2 upregulation and IL-9 production; and has a potential benefit in pulmonary fibrosis Might inhibit regulatory T cell activity
T193 45860-46071 Sentence denotes Anti-connective tissue growth factor (eg, pamrevlumab) CTGF, TGFβ pathway Fibroblasts, pericytes, endothelial cells, cardiomyocytes Potential benefit in pulmonary fibrosis Might be effective only at later stages
T194 46072-46438 Sentence denotes Receptor tyrosine kinase inhibitors (eg, nintedanib) Vascular endothelial growth factor, platelet-derived growth factor, and fibroblast growth factor receptors Fibroblasts, pericytes, endothelial cells, cardiomyocytes Approved for treating pulmonary fibrosis Might be effective only at later stages and correct timing is unclear; frequent diarrhoea; risk of bleeding
T195 46439-46572 Sentence denotes Pirfenidone TGFβ pathway M2 macrophages, fibroblasts Approved for treating pulmonary fibrosis Might be effective only at later stages
T196 46573-46590 Sentence denotes A2A=adenosine 2A.
T197 46591-46624 Sentence denotes CCR=C-C motif chemokine receptor.
T198 46625-46656 Sentence denotes CCL=C-C motif chemokine ligand.
T199 46657-46694 Sentence denotes CTGF=connective tissue growth factor.
T200 46695-46722 Sentence denotes CXCL=C-X-C motif chemokine.
T201 46723-46759 Sentence denotes CXCR=C-X-C motif chemokine receptor.
T202 46760-46785 Sentence denotes GATA=GATA-binding factor.
T203 46786-46842 Sentence denotes GM-CSF=granulocyte-macrophage colony-stimulating factor.
T204 46843-46874 Sentence denotes H1 receptor=histamine receptor.
T205 46875-46890 Sentence denotes IFN=interferon.
T206 46891-46906 Sentence denotes IL=interleukin.
T207 46907-46941 Sentence denotes ILC2=type 2 innate lymphoid cells.
T208 46942-46959 Sentence denotes JAK=Janus kinase.
T209 46960-46995 Sentence denotes MAS=macrophage activation syndrome.
T210 46996-47048 Sentence denotes NLRP=NACHT, LRR, and PYD domains-containing protein.
T211 47049-47088 Sentence denotes SOCS=suppressor of cytokine signalling.
T212 47089-47106 Sentence denotes ST2=ST2 receptor.
T213 47107-47138 Sentence denotes TGF=transforming growth factor.
T214 47139-47151 Sentence denotes Th=T-helper.
T215 47152-47179 Sentence denotes TNF=tumour necrosis factor.
T216 47180-47226 Sentence denotes TRIF=TIR domain-containing adapter molecule 1.
T217 47228-47238 Sentence denotes Conclusion
T218 47239-47556 Sentence denotes Upon increasing release of alarmin IL-33 from injured respiratory cells, in the lack of interferon expression, and alongside efforts of the immune system to overcome inefficient natural killer cells, cytotoxic T lymphocytes, and Th1 antiviral responses, sequential compensatory secretion of IL-2 family cytokines (ie.
T219 47557-47889 Sentence denotes IL-4, IL-9, IL-2, IL-7) from dysregulated GATA3+ Treg cells, differentiated ILC2, and overstimulated antigen-presenting cells might account for the early expansion of polyfunctional (CXCR3+)Vγ9Vδ2 T cells and the later expansion of (CCR2+CCR5+) GM-CSF-producing lymphocytes, both recruited to the lungs by specific chemoattractants.
T220 47890-47970 Sentence denotes These cells amplify alveolar damage and establish autoinflammatory lung disease.
T221 47971-48283 Sentence denotes At advanced stages of COVID-19, intense activation of the NLRP3 inflammasome and TLR2–MyD88–NF-κB mediated pathways most likely create a cytokine environment enriched in IL-1β, IL-23, IL-6, and TNF, which would further elicit Th17 differentiation and GM-CSF production by γδT17, Th17, and CD8 T cells (figure 1).
T222 48284-48541 Sentence denotes Ultimately, the resulting cytokine and chemokine milieu could account for the hyperinflammatory state of tissues and vessels mediated by dysfunctional endothelial cells, mast cells, monocyte-derived macrophages, and extracellular trap-producing neutrophils.
T223 48542-48700 Sentence denotes Endothelial release of tissue factor induced by IL-33, activated γδT cells, and neutrophil extracellular traps might act to promote thrombotic manifestations.
T224 48701-48981 Sentence denotes In patients who survive acute COVID-19, IL-33 might finally drive pulmonary fibrosis by activating M2 macrophages, ILC2, and mast cells to release TGFβ and IL-13, which act in turn on fibroblasts and type 2 pneumocytes to elicit an epithelial-to-mesenchymal transition (figure 2).
T225 48982-49210 Sentence denotes As a result, different stages of COVID-19 disease can be distinguished (ie, mild-to-moderate, severe-to-critical, chronic-to-fibrotic), and we suggest that IL-33 plays a central role in all of these pathogenic phases (figure 3).
T226 49211-49469 Sentence denotes A preprint101 that recently appeared online supports our model, revealing that SARS-CoV-2 peptide exposure elicits IL-33 expression from patients who are virus seropositive, and IL-33 production is correlated with T-cell activation and lung disease severity.
T227 49470-49652 Sentence denotes Targeting the IL-33–ST2 axis using monoclonal antibodies (or, alternatively, small-molecule inhibitors) could prove to be an effective strategy for controlling the COVID-19 pandemic.
T228 49654-49692 Sentence denotes Search strategy and selection criteria
T229 49693-50345 Sentence denotes We searched PubMed and Google Scholar for articles published in English from Jan 1, 2020, to July 31, 2020, using the search terms “COVID-19”, “coronavirus“, “IL-33”, “ST2”, “type-2 innate lymphoid cells (ILC-2)”, “gamma delta T cells”, “T cells”, “macrophages”, “mast cells”, “neutrophils”, “endothelial cells”, “adipocytes”, “IL-17”, “IL-7 “, “IL-9”, “GM-CSF”, “cytokines”, “chemokines”, “bronchoalveolar lavage fluid (BALF)”, “lung”, “heart”, “hyperinflammation”, “vasculitis”, “thrombosis”, “adult respiratory distress syndrome (ARDS)”, “hemophagocytic lymphohistiocytosis (HLH)”, “macrophage activation syndrome (MAS)”, “obesity”, and “treatment”.
T230 50347-50362 Sentence denotes Acknowledgments
T231 50363-50406 Sentence denotes There was no funding source for this study.
T232 50408-50420 Sentence denotes Contributors
T233 50421-50506 Sentence denotes GZ searched the literature, wrote the manuscript, and designed the figures and table.
T234 50507-50536 Sentence denotes PLC organised the manuscript.
T235 50538-50562 Sentence denotes Declaration of interests
T236 50563-50597 Sentence denotes We declare no competing interests.