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
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