In their study, Holtzman and colleagues use a new mouse model in which an acute airway infection with Sendai virus later switches to a chronic respiratory disease with features of asthma and COPD, namely, increased mucus production and airway hyperreactivity. In this setting, the innate immune system is thought to be active during the acute response to infection, whereas the adaptive immune system should be activated during the chronic phase of inflammatory disease. However, the authors found that the chronic respiratory disease occurred independently of the adaptive immune response. Instead, the disease was shown to depend on increased levels of the pro-inflammatory cytokine interleukin-13 (IL-13) produced by a previously undescribed innate immune pathway. The authors found that lung macrophages were the main cellular source of IL-13 production. Moreover, when they studied the cause of macrophage activation, they found that iNKT cells were responsible for macrophage production of IL-13. The iNKT cells activated macrophages using IL-13–IL-13-receptor and CD1d–invariant-T-cell-receptor interactions. This process led to an alternatively activated phenotype for macrophages and ultimately resulted in chronic inflammatory lung disease. In translational work, the investigators demonstrated that iNKT cells and macrophages are also associated with IL-13 production in the lungs of humans with severe asthma and COPD.
Taken together, this study has identified an innate iNKT-cell–macrophage immune axis that enables a common type of viral infection to give rise to a chronic inflammatory disease. The findings provide insight into a new molecular phenotype for inflammatory disease of the lungs and possibly other organs, and could thereby allow for more precise diagnosis and specifically tailored treatment of chronic disease in humans.
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