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.