Rhinovirus infections – IL-33
A recent Journal of Translational Medicine study indicates that interleukin (IL)-33 is produced by bronchial smooth muscle cells (BSMCs) upon rhinovirus (RV) infection and activation of TLR3, and that this response is associated and/or mediated by ATP released by viral-stimulated BSMCs.
Interleukin-33 is a member of the IL-1 family. This cytokine was originally described as an inducer of type 2 immune responses, activating T helper 2 (TH2) cells and mast cells. Interleukin-33 is a ligand for ST2 (IL1RL1), an IL-1 family receptor that is highly expressed on Th2 cells, mast cells and group 2 innate lymphocytes.
Interleukin-33 also potently stimulates group 2 innate lymphoid cells (ILC2s), regulatory T (Treg) cells, TH1 cells, CD8+ T cells and natural killer (NK) cells. This pleiotropic nature is reflected in the role of IL-33 in tissue and metabolic homeostasis, infection, inflammation, cancer and diseases of the central nervous system.
Interleukin-33 is a cytokine constitutively expressed in epithelial barrier tissues, and implicated in allergic inflammation and asthma pathogenesis. Elevated levels of IL-33 have been demonstrated in situ in bronchial epithelium as well as bronchial smooth muscle cells from subjects with severe asthma, implicating IL-33 in asthma pathogenesis.
Broad expression in stromal and barrier tissue renders IL-33 a ubiquitous and crucial immune modulator that shapes type 1, type 2 and regulatory immune responses.
New evidence indicates that innate lymphoid cells (ILC2s) are most likely the major targets of IL-33. Thus, after release, IL-33 activates ILC2s, which secrete large amounts of IL-5 and IL-13. In addition, IL-33 also stimulates regulatory T (Treg) cells, Th1 cells, CD8+ T cells and natural killer (NK) cells.
Previous research indicates that IL-33 functions as an alarm signal (alarmin) released upon tissue damage, exposure to allergens or infection with viruses or parasites. More recent data suggests, however, that the IL-33 alarmin function is mediated via autocrine release of ATP and purinergic P2-receptor (P2R) activation.
ATP is a ‘classical neurotransmitter’, including a neuromediator at the brain-immune interface, but ATP may also serves as a ‘danger signal’ to alert the immune system of tissue damage.
The involvement of the ATP/P2R axis in pulmonary inflammation and asthma is substantiated by the presence of increased levels of ATP in the airways of patients with asthma and chronic obstructive pulmonary disease (COPD). Importantly, exposure to aeroallergens induces rapid extracellular release of ATP, associated with an instant release of IL-33 into the airway lumen.
In the Journal of Translational Medicine study Jenny Calvén and colleagues from the Department of Experimental Medical Science, Lund University, Lund, Sweden report that IL-33 is produced upon RV infection and activation of TLR3 by double-stranded (ds)RNA of primary human BSMCs from healthy and asthmatic subjects.
In this study extracellular ATP levels were increased rapidly after stimulation of BSMCs with dsRNA and elevated in supernatants from RV-infected BSMCs.
Importantly, ATP appear to mediate the release of IL-33 by BSMCs since ATP is produced upon RV infection and TLR3 activation, and the ATP secretion is blocked, in a concentration-dependent manner, by the broad inhibitor of purinergic signaling suramin.
The study of Calvén et al. suggests that rhinovirus (RV) infections contribute to an increased expression and production of IL-33 by bronchial smooth muscle cells (BSMCs). In this process, the authors suggests that ATP, most likely epithelial-derived may promote and mediate the IL-33 expression, and the ATP/P2R-axis may play an important role in the viral stimuli-induced effects directly on BSMCs.
In conclusion, this study indicates that epithelial mediators may induce baseline BSMC IL-33 gene expression and that augmented expression and production of IL-33 are caused by RV infection of BSMCs and stimulation of TLR3 and RIG-I-like receptors. In this process, the ATP/P2R-axis may be involved in the present viral stimuli-induced effects directly on BSMCs.
Source: J Transl Med. 2015; 13: 281.
Read more: Journal of Translational Medicine
Updates
2022a
A 2022 study Charlene Akoto et al. investigated the global response of mast cells (MCs) to IL-33 stimulation and determined whether this had a functional consequence during viral infection.
The authors found that IL-33 induced an antiviral signature in MCs but rather than providing protection against human rhinoviruses (HRVs) infection, IL-33 increased the infection of MC by HRV by causing upregulation in ICAM1, the receptor used by HRV16 for cellular entry.
The investigators concluded that their study identified a potential gene-environment interaction involving the effect of IL-33 and HRV on MC that may have important consequences in virus-induced exacerbations of asthma.
2022b
A 2022 systematic review by Kong Yen Liew et al. included thirty-four articles, with 18 of these further subjected to meta-analysis, aimed to identify cytokines/chemokines that play an essential role in the pathogenesis of Rhinovirus (RV) infections-induced asthma exacerbations.
Background: The authors briefly discuss data from epidemiological studies indicating that RV infections were frequently found to be associated with a majority of exacerbations of asthma in adults as well as children. Of note, as per a recent meta-analysis by Feddema and Claassen, RV is the most commonly detected virus in asthmatics; while Corne and colleagues have demonstrated that while asthmatic and healthy subjects in a longitudinal cohort study had a similar frequency of upper respiratory RV infections, asthmatic subjects had more frequent, severe, and longer-lasting lower respiratory tract symptoms.
Results: Several studies reported the correlations between the levels of cytokines, such as IL-8, IL-4, IL-5, and IL-13, and respiratory symptoms.
Evidence suggested that IL-25 and IL-33 may be the cytokines that promote type 2 inflammation in asthmatics after RV infection, and maybe are key cytokines driving the type 2 inflammatory responses in asthmatic airways
The authors also confirmed that the reduced ability of asthmatic airway epithelial cells to secrete IFNs. Thus, given the immunomodulatory role of interferons (IFNs) in promoting the Th1 phenotype of CD4 T cells, the defective innate immune responses in airway epithelium – the primary site of RV infection and replication – might lead to a skewed Th2 response and an enhanced type 2 inflammation in asthmatic airways.
The authors concluded that RV-induced asthma exacerbations are potentially caused by enhanced Th2 responses (IL-4, IL-5, and IL-13), which could be promoted by IL-25 and IL-33, and IL-15 deficiency before RV infection. The imbalance between Th1 and Th2 cytokines in the airways during RV-induced asthma exacerbations may be partly contributed by defective innate immune responses in airway epithelial cells and reduced IFNs (IFN-β and IFN-λ) production.
Cover Image Credit: Graphical abstract, from: IL-33-induced neutrophilic inflammation and NETosis underlie rhinovirus-triggered exacerbations of asthma by Bodie Curren et al. Mucosal Immunol. 2023 Oct;16(5):671-684. doi: 10.1016/j.mucimm.2023.07.002
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