In December 2019, an outbreak caused by Coronavirus disease 2019 (COVID-19) occurred in Wuhan, Hubei province, China [1]. SARS-CoV-2 is a positive single-stranded enveloped RNA virus (ssRNA) that belongs to the beta-coronavirus genus of the Coronaviridae family [2]. As with other infections caused by respiratory viruses, a process of recognition by cytotoxic T lymphocytes also occurs following SARS-CoV-2 infection, resulting in the overproduction of a wide range of proinflammatory mediators, known as a “cytokine storm” (CS), an uncontrolled production of soluble inflammatory markers that, in turn, support an aberrant systemic inflammatory response, which seems to be the main cause of the clinical severity of respiratory infection, up to acute respiratory distress syndrome (ARDS). Mast cells and basophils also appear to be involved in the genesis of CS; their activation, in fact, would be able to determine the procoagulant state characteristic of this type of infection ^[2][3][2,3]. In this context, the alarmin known as interleukin-33 (IL-33), traditionally involved in allergic and autoimmune diseases (such as rheumatoid arthritis, systemic sclerosis, atopic dermatitis and food allergies), assumes a role of particular interest, as it is involved in pro-inflammatory processes [4]. IL-33 acts by binding to a receptor complex known as the accessory protein of the ST2 and IL-1 receptor, expressed on a series of innate and adaptive immune cells, to initiate inflammatory pathways dependent on the myeloid differentiation factor 88 (MyD88) response and exerting pleiotropic effects [5]. The soluble form of ST2, as a down-regulation mechanism of IL-33, has been identified as a reliable biomarker of poor prognosis in cardiovascular disease, acute respiratory distress syndrome (ARDS) and other inflammatory conditions. For example, in children with acute lower respiratory infection (ALRI), local activation of the IL-33/ST2 axis has been shown to be associated with a more severe disease evolution, with the need for ventilatory support [6]. More recently, a link has been discovered between IL-33 and lung damage in pulmonary viral infections and chronic lung diseases. In fact, IL-33 is known to increase airway inflammation, mucus secretion and Th2 cytokine synthesis in the lungs, following respiratory infections such as influenza virus, RSV and rhinovirus infection [7]. However, IL-33 can also stimulate the activity of antiviral cytotoxic T cells and the production and release of antibodies [7]. Similarly to other respiratory virus infections, exposure to the SARS-CoV-2 peptide also causes IL-33 expression, correlating with T cell activation and lung disease severity. Although the increase in IL-33 levels is considered a predictor of severe COVID-19, its precise role at different stages of the disease is still unclear. However, the activation role of IL-33 on antiviral CD8 T cells, with consequent possible elimination of the virus in long-lasting infections, is known. As a result, targeting the IL-33-ST2 axis using monoclonal antibodies could prove to be an effective strategy for controlling the COVID-19 pandemic ^[8][9][10][8,9,10].

2. IL-33: Synthesis, Receptor Effects and Pathogenetic Role in Respiratory Diseases

IL-33 is a nuclear cytokine derived from tissues of the IL-1 family. It is found widely expressed in various cells of the human body, including endothelial, epithelial and fibroblast-like cells. Its function is that of an alarm signal (alarmin), released in the event of cell or tissue damage to alert the immune cells that express the ST2 receptor (IL-1RL1) [11]. IL-33 is a dual-function cytokine based on the size of its structure: the full-length IL-33 protein (flIL-33) acts as a regulator of the intranuclear gene, while mature IL-33 (mIL-33) is released as a result of cell damage or necrosis. Both forms, flIL-33 and mIL-33, can bind and signal through ST2, which is predominantly expressed by immune cells involved in innate immunity, including mast cells, ILC2, macrophages, basophils, natural killer cells (NK cells), dendritic cells (DC), and eosinophils. Furthermore, ST2 is expressed by cells that participate in adaptive immunity, such as CD4+, CD8+ T cells, and T-regulatory cells (Tregs) [12]. By binding to ST2, IL-33 activates target cells and stimulates them to secrete cytokines and growth factors that promote and/or regulate local and systemic immunity [13]. Once bound to the ST2 receptor, IL-33 intensely stimulates the production of Th2-associated proinflammatory cytokines, including IL-4, IL-5, and IL-13 [14]. Regarding chronic respiratory diseases, IL-33 concentrations have been shown to be significantly elevated in the sputum and bronchoalveolar lavage fluid (BALF) of patients with bronchial asthma. In these patients, IL-33 causes a wide range of effects, including neutrophil migration, mast cell activation, osteoclast and osteoblast function, wound healing, and others [15].

3. Role of IL-33 in Rhinovirus Infection

Rhinovirus (RV) is a positive-sense single-stranded RNA virus, classified into rhinovirus A and rhinovirus B based on differential susceptibility to capsid-binding compounds, both subtypes that use ICAM-1 as cellular entry receptor ^[16][22]. In non-asthmatic individuals, symptoms of infection are usually confined to the upper respiratory tract, whereas in patients suffering from asthma or other respiratory diseases, symptoms affecting the lower respiratory tract are more frequent, such as cough, shortness of breath, chest tightness and wheezing ^[17][52]. RV-induced exacerbations in asthmatics have been linked to the defective expression of protective interferons of type I and III in epithelial cells, which are also responsible for the production of various inflammatory mediators, responsible for Th2-based stimulation and, therefore, susceptibility to development of acute allergic inflammation of the airways ^[18][19][20][23,25,27]. Epithelium-derived “innate cytokines” include IL-25 (or IL-17E), IL-33, and thymic stromal lymphopoietin (TSLP), which are produced in response to RV infection and play a role in the maturation of Th2 cells through activation of dendritic cells ^[21][22][24,26]. In this regard, Jurak LM et al. ^[23][28], demonstrated that in asthmatic subjects, IL-33 stimulates type-2 inflammatory responses to RV, but has little effect on type-1 immune responses, probably as a consequence of the differential regulation of the IL-33 receptor with increased expression of the ST2 form in asthmatic cells. Furthermore, the same study also showed how RV and IL-33 act together to increase IFNγ production by NK cells. Several studies conducted in vitro on bronchial epithelial cells and in vivo on mouse models have shown how the production of IL-33 following RV infection is determined by the activation of two specific signaling pathways: that mediated by toll-like receptors 3 (TLR3) and 2 (TLR2). These are in turn responsible for the secretion of specific chemokines such as CXCL-10, resulting in the recruitment of macrophages into the lung and the development of inflammation ^{[24][25][26][27]}[29,32,53,54]. In asthmatics, IL-33 would also be able to facilitate viral capture by the pulmonary vascular endothelium by the expression of ICAM-1, thus intensifying the inflammation orchestrated by the endothelium (from IL-1β, IL-6), promoting the growth (from G-CAS, GM CSF) and recruitment of mostly innate immune cells: neutrophils and eosinophils ^[28][31]. In consideration of the role that IL-33 plays in the severe asthma exacerbations evoked by rhinovirus, this makes it one of the potential targets of anti-IL-33 monoclonal antibody biotherapy. Blocking IL-33, in fact, attenuates respiratory inflammation in all phases of the infection, suppressing type-2 inflammation, restoring antiviral immunity, and increasing viral clearance ^[29][30][31][18,39,40].