IL-27 and IFN-Gamma & Resistance in Asthma
The mechanisms driving steroid resistance in asthma are poorly understood, but a new study published in Journal of Immunology indicates that a novel interleukin (IL)-27– and interferon (IFN)-γ–driven pathway may contribute to this process, where the activation of MyD88-dependent pathways in macrophages may play a critical role.
The major downstream molecules that regulate IFN-gamma and LPS-TLR4/MyD88–mediated inflammation and steroid resistant airway hyperresponsiveness (AHR) remain unknown.
A recently discovered member of the IL-6/IL-12 family, IL-27, is a heterodimeric cytokine that has two subunits – an EBV-induced gene 3 (EBI3) and a p28 chain.
IL-27 is known to promote IFN-gamma production by Th1 cells, as well as innate host defense responses to infection, both of which may contribute to severe forms of asthma and exacerbations.
In the Journal of Immunology study, J Li and co-workers show that IL-27 production in macrophages plays a critical role in this mechanism of steroid resistance, by signaling with IFN-gamma.
Importantly, the effects of IL-27/IFN-gamma are mediated via a novel MyD88-dependent pathway that suppresses nuclear translocation of the glucocorticoid receptor in pulmonary macrophages.
The authors discuss recent studies suggesting that Th2 cell/eosinophil–dominated asthma, which is dependent on signaling through STAT6, can be effectively managed by steroids, whereas pathways activated by host defense mechanisms (classically nonallergic) such as IL-27/IFN-gamma and Th17 cells are more likely to be steroid-resistant.
IL-27 and IFN-γ were expressed to a greater extent in the airway secretions of neutrophilic asthmatics, who show insensitivity to steroid treatment, and as discussed there, neutrophilic airway inflammation is a recognized feature of severe and difficult-to-manage asthma.
The authors conclude that the novel mechanism, revealed in this study, and which does not require eosinophilic or neutrophilic inflammation and occurs independently of T lymphocytes, may be clinically relevant.
Moreover, understanding the contribution of this novel macrophage pathway to subtypes of asthma may provide new therapeutic approaches for treatment-resistant asthma.
SOURCE: J Immunol 2010, 185: 4401
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An Update
A 2018 study classifies IFN-γ and IL-27 as critical regulators of respiratory syncytial virus (RSV)–induced exacerbation of allergic airways disease in a mouse model. It is known that stimulation of pulmonary macrophages with TNF-α and/or MCP-1 induces an expression of both IFN-γ and IL-27. Thus, this study identifies a mechanism, downstream of TNF-α and MCP-1, controlling RSV-induced asthma exacerbations.
Background: Respiratory syncytial virus (RSV) causes lower respiratory tract infections and bronchiolitis in children but also increases susceptibility to development of asthma, and is an important trigger (with rhinovirus and parainfluenza viruses) of asthma exacerbations. Glucocorticoid therapy effectively controls mild-to-moderate asthma, but it often fails to improve symptoms in patients with asthma exacerbations. Of note, glucocorticoids treatment, for example with dexamethasone (Dex) shows no beneficial effect for the treatment of children with RSV-induced bronchiolitis.
It is also known that the expression of IFN-γ is significantly increased in airways of patients with severe asthma, who often respond poorly to glucocorticoid treatment, while the levels of IL-27 are increased in bronchoalveolar lavage fluid (BALF) cells of severe asthmatic patients. In addition, LPS and IFN-γ, collectively induce the production of IL-27, the activation of neutrophils and macrophages.
At BrainImmune, we have also reported some insights into mechanisms driving stress-induced increased susceptibility to viral infections and the link between viral infections, psychological stress and asthma exacerbations.
The 2018 study found a significant increase in IFN-γ and IL-27 levels in lung tissues and in isolated pulmonary macrophages following RSV inoculation in mice. The expression of IFN-γ and IL-27 was resistant to Dex treatment, which potentially links both cytokines to the development of asthma exacerbations. Of note, previous clinical and experimental data suggest that IFN-γ by cooperating with IL-27 may play an important role in the induction of steroid resistance in asthma following viral infection–induced exacerbations.
The authors treated mice with anti–IFN-γ Ab, and in their model of RSV-induced exacerbation they observed that anti–IFN-γ Ab treatment completely abolished steroid-resistant exaggerated AHR and reduced the levels of infiltrating macrophages and neutrophils to almost baseline levels. Furthermore, they found that stimulation of pulmonary macrophages with TNF-α and/or MCP-1 could induce IFN-γ and IL-27 production, suggesting a mechanistic link with previous studies.
Thus, overall, these observations suggest that targeting signaling pathways activated by the cooperative interaction between IFN-γ/IL-27 could be a potential approach for the treatment of RSV-induced exacerbation of asthma.
