Table 1.
Research articles analyzed and their main results.
| Author | Year | Type of Study | Objective | Outcome |
|---|---|---|---|---|
| Ronan Le Goffic et al. [11] | 2011 | Research study | Evaluation of IL-33 expression and release in lungs of influenza A virus-infected mice in vivo and in murine respiratory epithelial cells | Significant increase in mRNA expression of IL-33 in the virus-infected mice at day 3, compared with non-infected control mice. A significant correlation was found between IL-33 mRNA induction and mRNA levels of TNF-a, IFN-g, and IL-6, but not with IL-1b. The protein expression of IL-33 in virus-infected lungs and in BAL was significantly higher than in controls, especially at day 3. We found a significant increase in IL-33 mRNA expression in IAV-infected transformed murine respiratory epithelial cell line, MLE-15, and human pulmonary epithelial cell line A549, compared with non-infected cells. |
| Jia-Rong Bian et al. [12] | 2014 | Research study | Evaluation of serum levels of pro-inflammatory cytokines in adult patients with seasonal influenza infection | Higher serum concentration of IL-6, IL-33, and TNF-α at admission, compared to controls. Higher levels of IL-33 were found in influenza A-infected patients. |
| Kayamuro H et al. [13] | 2010 | Research study | Evaluation of specific antibody response and specific cellular toxicity in intranasally immunized mice with hemagglutinin and various cytokines | IL-1 family cytokines were able to induce the highest IgG and IgA production. IL-33 and IL-18 were able to elicit both Th1- and Th2-type cytokine responses and high-avidity CD8+ cytotoxic lymphocytes. |
| Xi-zhi J. Guo et al. [14] | 2018 | Research study | Evaluation of γδ T cells and production of IL-33 in mouse models of influenza infection | IL-33 induces a local type-2 immune response with increased accumulation of type-2 innate lymphoid cells and T regulatory cells in the lung, which promotes tissue repair and lung integrity after influenza infection. |
| Monticelli et al. [15] | 2011 | Research study | Evaluation of the role of innate lymphoid cells after influenza virus infection | Innate lymphoid cells, induced by IL-33, are of crucial importance in promoting airway epithelial integrity and lung tissue homeostasis through production of the epidermal growth factor family member amphiregulin. |
| Robinson et al. [16] | 2018 | Research study | Evaluation of the role of IL-33 in mucosal anti-bacterial host defense in influenza infection and bacterial superinfection | Reduction in IL-33 correlates with a negative outcome after influenza infection and bacterial superinfection. Its restoration is correlated with an improvement in bacterial clearance, not related to innate lymphoid cells or type-2 macrophages but to neutrophil recruitment. |
| Chae Won Kim et al. [17] | 2019 | Research study | Evaluation of antiviral protection against influenza virus infection by exogenous IL-33 | Exogenous administration of IL-33 was related to a better outcome in mice infected with influenza IL-33 virus. IL-33 increased the number of innate lymphoid cells, eosinophils, and dendritic cells and CD8+ T-cell activity. |
| García-García ML, Calvo C et al. [18]. | 2017 | Experimental study | Investigate whether infants exhibit enhanced nasal airway secretion of TSLP, IL-33, and periostin during natural respiratory viral bronchiolitis | Bronchiolitis caused by common respiratory viruses is associated with elevated nasal levels of TSLP, IL-33, and periostin, factors known to be important in the development of Th2-response. |
| Mehta AK, Duan W et al. [19] | 2016 | Experimental study | Examine whether rhinovirus infection of the respiratory tract can block airway tolerance by modulating Treg cells | Infection of the respiratory epithelium with rhinovirus can antagonize tolerance to inhaled antigen through combined induction of TSLP, IL-33, and OX40 ligand, and this can lead to susceptibility to asthmatic lung inflammation. |
| Jarjour NN, Esnault S [20] | 2014 | Review | Demonstrate the mechanism of exacerbation in human asthma during rhinovirus infection | IL-33 is likely a major cause of viral-induced asthma exacerbations and a potential therapeutic target in asthma. |
| Jackson DJ, Makrinioti H et al. [21] | 2014 | Experimental study | Assess whether rhinovirus induces a type-2 inflammatory response in asthma in vivo and define a role for IL-33 in this pathway | IL-33 and type-2 cytokines are induced during a rhinovirus-induced asthma exacerbation in vivo. |
| Han M, Rajput C et al. [22] | 2017 | Experimental study | IL-33 and TSLP expression is also induced by RV infection in immature mice and required for maximum ILC2 expansion and mucous metaplasia | The generation of mucous metaplasia in immature, RV-infected mice involves a complex interplay between the innate cytokines IL-25, IL-33, and TSLP. |
| Jurak LM, Xi Y et al. [23] | 2018 | Case-control study | Investigate the effects of IL-33 on rhinovirus (RV)-induced immune responses by circulating leukocytes from people with allergic asthma, and how this response may differ from non-allergic controls | RV infections and IL-33 might interact in asthmatic individuals to exacerbate type-2 immune responses and allergic airway inflammation. |
| Calvén J, Akbarshahi H et al. [24] | 2015 | Experimental study | Investigate effects of epithelial-derived media and viral stimuli on IL-33 expression in human BSMCs | RV infection of BSMCs and activation of TLR3 and RIG-I-like receptors cause expression and production of IL-33. |
| Ramu S, Calvén J et al. [25] | 2020 | Case-control study | Compare levels of RV-induced IL-33 in BSMCs from healthy and asthmatic subjects | RV infection cause higher levels of IL-33 and increased pro-inflammatory and type-2 cytokine release in BSMCs from patients with non-severe asthma. |
| Ganesan S, Pham D et al. [26] | 2016 | Experimental study | Examine the role of TLR2 and IRAK-1 in RV-induced IFN-β, IFN-λ1, and CXCL-10, which require signaling by viral RNA | RV stimulates CXCL-10 expression via the IL-33/ST2 signaling axis, and TLR2 signaling limits RV-induced CXCL-10 via IRAK-1 depletion at least in airway epithelial cells. |
| Gimenes JA Jr, Srivastava V et al. [27] | 2019 | Experimental study | Examine the mechanisms underlying the RV-induced persistent inflammation and progression of emphysema in mice with COPD phenotype | RV may stimulate expression of CXCL-10 and IFN-γ via activation of the ST2/IL-33 signaling axis, which in turn promotes accumulation of CD11b+/CD11c+ macrophages and CD8+ T cells. |
| Gajewski A, Gawrysiak M et al. [28] | 2019 | Experimental study | Analyze the effect of IL-33, the cytokine widely distributed in large amounts in airways of asthmatic individuals, on the HRV-induced inflammatory response in the human lung vascular endothelium. | In asthmatics, IL-33 may facilitate higher viral load in the lung vascular endothelium, while IL-33-orchestrated cytokine milieu may enhance innate inflammatory responses without any concomitant increase in antiviral innate and adaptive mechanisms. |
| Werder RB, Zhang V et al. [29]. | 2018 | Experimental study | Determine whether anti-IL-33 therapy is effective during disease progression, established disease, or viral exacerbation using a preclinical model of chronic asthma and in vitro human primary airway epithelial cells (AECs) | The latter phenotype was replicated in rhinovirus-infected human AECs, suggesting that anti-IL-33 therapy has the additional benefit of enhancing host defense |
| Han Xu et al. [30] | 2017 | Research Study | Evaluation of the role of natural helper cells in influenza virus-induced airway hyper-responsiveness | Blockage of IL-33 reduces natural helper cell recruitment in lungs, thus suggesting IL-33 is necessary for activating Th2-type response. |
| Wu Yi-Hsiu et al. [7] | 2019 | Research study | Evaluation of the individual roles of IL-33-activated innate immune cells, including ILC2s and ST2+ myeloid cells, in RSV infection-triggered pathophysiology. | IL-33 is crucial for the activation of ILC2s and the development of airway hyperreactivity and airway inflammation. IL-33 through lung myeloid cells mediates cellular infiltration but not airway hyperreactivity. |
| Liwen Zhang et al. [31] | 2021 | Research study | Investigation of the role of NF-κB/IL-33/ST2 axis on RSV-induced acute bronchiolitis | IL-33 level was significantly elevated in infants with RSV acute bronchiolitis. The NF-κB/IL-33/ST2 axis is important in the establishment of the Th2 environment after RSV infection. The use of an anti-IL-33 antibody blocks that mechanism, thus suggesting the crucial role of IL-33, especially produced by macrophages. |
| Allison E. Norlander and R. Stokes Peebles, Jr. [32] | 2020 | Review | Review of the impact of L-33, IL-25, thymic stromal lymphopoietin (TSLP), and high mobility group box 1 after RSV infection | ILC2 activation leads to the production of type-2 cytokines and the induction of a type-2 response during RSV infection. |
| Carolina Augusta Arantes Portugal et al. [6] | 2020 | Research study | Assess the role of IL-33-ST2 axis in acute lower respiratory infection by RSV | IL-33 and ST2 in nasopharyngeal aspirates on admission were associated with higher risk for mechanical ventilation. |
| Jing Liu et al. [33] | 2015 | Research study | Evaluation of IL-13-IL-33-ST2 axis and natural helper cells in the development of RSV-induced airway inflammation | RSV infection induces an increase in the number of IL-13-producing natural helper cells in an IL-33-dependent pathway. |
| Jordy Saravia et al. [34] | 2015 | Research Study | Evaluation of the pathogenic mechanisms responsible for RSV-induced immunopathophysiology | Infection with RSV induced rapid IL-33 expression and an increase in ILC2 numbers in the lungs of neonatal mice, in contrast with adult mice. Blocking IL-33 during infection was sufficient to inhibit RSV airway hyperresponsiveness, Th2 inflammation, eosinophilia, and mucus hyperproduction, whereas administration of IL-33 to adult mice during RSV infection was sufficient to induce RSV disease. Elevated IL-33 and IL-13 were observed in nasal aspirates from infants hospitalized with RSV. |
| Feifei Qi et al. [35] | 2015 | Research study | Evaluation of cellular source of IL-33, particularly the types of IL-33-producing cells in innate immune cells during RSV infection | IL-33 plays a key role in RSV-induced airway inflammation. Alveolar macrophages and dendritic cells are a cellular source of IL-33. RSV infection increases expression of IL-33 in pulmonary dendritic cells but not in interstitial macrophages. Macrophages and dendritic cells mediate the production of IL-33 through interaction with TLR3 or TLR7. |
| Feifei Qi et al. [36] | 2017 | Research study | Evaluation of specific signaling pathways for activation of macrophages during RSV infection | RSV infection can promote both the expression of mRNAs for MAPK molecules and the levels of MAPK proteins in lung macrophages. This mechanism may participate in the process of RSV-induced IL-33 secretion by macrophages, demonstrated by an attenuation of IL-33 production when mice were treated with a special MAPK inhibitor before RSV infection. |
| Stier MT et al. [37] | 2016 | Research study | Determination of the capacity of RSV infection to stimulate group 2 innate lymphoid cells (ILC2s) and the associated mechanism in a murine model | RSV-infected IL-33 knock-out mice presented a reduced lung concentration of IL-13, thus highlighting an important role for IL-33 in ILC2 activation. |
| Zeng S. et al. [38] | 2015 | Research study | Evaluation and understanding of the function of IL-33/ST2 signaling pathway during respiratory syncytial virus (RSV) infection | Following intranasal infection with RSV, BALB/c mice showed a marked increase in the production of IL-33, with elevated expression of ST2 mRNA as well as a massive infiltration of CD45+ST2+ cells in the lungs, suggesting that during the early phase of RSV infection, IL-33 target cells, which express ST2 on cell surface, may play a critical role for the development of RSV-induced airway inflammation. Indeed, blocking ST2 signaling using anti-ST2 monoclonal antibody diminished not only RSV-induced eosinophil recruitment, but also the amounts of Th2-associated cytokines, particularly IL-13, and Th17-type cytokine IL-17A in the lungs of infected mice. |
| Bertrand P. et al. [39] | 2015 | Research study | Evaluation of possible mechanisms that connect RSV bronchiolitis to asthma and recurrent wheezing | Patients with family history of atopy presented a high level of IL-33 in nasopharyngeal aspirates. |
| García-García ML et al. [18] | 2017 | Research study | Assessment of the role of thymic stromal lymphopoietin, IL-33, and periostin in viral bronchiolitis | Infants with bronchiolitis had higher levels of TSLP (p = 0.02), IL-33 (p < 0.001) and periostin (p = 0.003) than healthy controls. TSLP and IL-33 were more common in coinfections, mainly RSV and rhinovirus, than in single-infections (p < 0.05). |
| Vu et al. [40] | 2019 | Research study | Investigate the role of mucosal innate immune responses to RSV and respiratory viral load in infants hospitalized with the natural disease | Levels of IL-4, IL-13, IL-33, and IL-1β were significantly higher in nasal aspirates of patients with severe disease compared with those of patients with moderate disease. The authors highlighted the prevalence of type-2 responses to RSV infection in infants and suggested an important role of ILC2 in shaping the immune response early during RSV infection. |
| Stav-Noraas TE et al. [41] | 2017 | Experimental study | Investigate whether endothelial IL-33 expression is augmented by adenoviral activation of the DNA damage machinery | Adenoviral transduction stimulates IL-33 expression in endothelial cells in a way that depends on the DNA-binding protein MRE11 and the antiviral factor IRF1 but not on downstream DNA damage response signaling |
| Zhang Y et al. [42] | 2018 | Experimental study | Evaluate the protective effects of Ad5-gsgAM in an ovalbumin (OVA)-induced asthmatic mouse model | Modulating the IL-33/ST2 axis via adenovirus-vectored mycobacterial antigen vaccination may provide clinical benefits in allergic inflammatory airways disease |
| Yin H et al. [43] | 2012 | Experimental study | Determine whether high levels of local soluble ST2 can ameliorate ovalbumin (OVA)-induced allergic airway inflammation | Single intranasal delivery of Ad-sST2-Fc to OVA-sensitized mice reduces significantly the production of Th2 cytokines, bronchoalveolar lavage eosinophil infiltrates and histopathological changes in the lung. Moreover, the protective effect is related to blocking IL-33/ST2L signaling. |
| Stanczak M.A. [44] | 2021 | Observational study | To analyze the seroprevalence and immune responses in subjects exposed to SARS-CoV-2 |
|
| Liang Y. [10] | 2021 | Original article, in vitro study | To test whether SARS- CoV-2 infection induces IL-33 expression in epithelial cells | IL-33 transcript levels significantly increased in cell lines at 72 h post-infection. |
| Burke H. [45] | 2020 | Observational study | To measure serum IL-6, IL-8, TNF, IL-1β, GM-CSF, IL-10, IL-33 and IFN-γ using a multiplex cytokine assay, in 100 hospitalized patients with COVID-19 | Increased IL-33 levels were associated with adverse outcomes. |
| Munitz A. [46] | 2021 | Original article | To investigate a correlation of IL-33 and IgG seroconversion with disease severity |
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| Gaurav R. [47] | 2021 | Observational-post mortem | To characterize IL-33 expression in the lungs of patients with fulminant COVID-19, compared with other inflammatory lung diseases |
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| Jeican I. [48] | 2021 | Original article | To perform a comparative morphological characterization of the respiratory nasal mucosa in CRSwNP versus COVID-19 and tissue IL-33 | The tissue IL-33 concentration in CRSwNP was higher than in COVID-19. |
| Markovic S. [49] | 2021 | Observational study | To analyze the correlation of IL-33 and other innate immunity cytokines with disease severity |
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| Zeng Z. [9] | 2020 | Original article | To study the role of soluble ST2 in COVID-19 and its relationship with inflammatory status and disease severity |
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