Rhinovirus Infections via ATP Release May Trigger IL-33 Production by Bronchial Smooth Muscle Cells: Implications for Asthma

Rhinovirus Infections via ATP Release May Trigger IL-33 Production by Bronchial Smooth Muscle Cells: Implications for Asthma

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.

IL-33 is a cytokine constitutively expressed in epithelial barrier tissues, and was originally described as a potent inducer of type 2 immune responses, activating T helper (Th) cells and mast cells, and implicated in allergic inflammation and asthma pathogenesis.

New evidence indicates, however, 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 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.

Source: J Transl Med. 2015; 13: 281.
Read more: Journal of Translational Medicine


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Source: Cover Image: IL-33 as an alarm signal (alarmin) and its role in allergic inflammation. From: Current Opinion in Immunology 2014, 31:31–37 by Corinne Cayro and Jean-Philippe Girard; Open Access; Public domain.

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