Chronic obstructive pulmonary disease (COPD) is characterized by chronic airway inflammation, mucus hypersecretion, and emphysema, which lead to reduced lung function and breathlessness. The pathologies of COPD are due to an abnormal immune response. Invariant natural killer T (iNKT) cells are an important population of innate lymphocytes and have been implicated in the regulation of immune responses associated with a broad range of diseases including COPD. We have here analyzed the role of iNKT cells in a model of COPD induced by repeated intranasal administration of iNKT cell agonist α-galactosylceramide (α-GalCer). Our results demonstrated that mice that received repeated intranasal administration of α-GalCer had molecular and inflammatory features of COPD including airway inflammation with significant increases in infiltration of macrophages and lymphocytes, CD8+ T cells, as well as proinflammatory cytokines IL-6 and TNF-α. In particular, these mice also showed the presence of pulmonary emphysema, mucus production, and pulmonary fibrosis. Furthermore, neutralization of IL-4 reduced α-GalCer induced emphysema. This study indicates the importance of iNKT cells in the pathogenesis of COPD by an IL-4 dependent mechanism.
Liver is an immunologically tolerogenic organ, while, autoreactive immune cells mediated autoimmune hepatitis (AIH) is observed. Suppression of the hyper-reactive immune responses may restore the tolerance of liver. IL-37, an emerging IL-1 family cytokine with anti-inflammatory effects on innate and adaptive immunity, shows benefit on many autoimmune diseases. We proposed IL-37 could inhibit immune responses and improve AIH. IL-37 expressing adeno-associated virus (AAV-IL-37) successfully dampened the activation of macrophages in vitro. We next analyzed the effect of IL-37 in Con A-induced autoimmune hepatitis mouse model. Surprisingly, the liver histopathology showed more necrotic hepatocytes and infiltrating immune cells in AAV-IL-37 treated Con A mice than in control mice. Higher levels of serum IFN-γ in IL-37-expressing Con A mice were observed. Moreover, expression of inflammation-related mRNA in the liver were also highly induced with AAV-IL-37 treatment. Among hepatic lymphoid cells, NK and NKT cells were particularly increased in IL-37 treated Con A mice. The frequency of IFN-γ-secreting NK cells was also significantly increased. Further, CCL5, a chemoattractant for NK cells, was significantly elevated in the serum of AAV-IL-37 injected Con A mice. These results suggest that IL-37 worsen liver inflammation instead of relieving the disease. Of note, there was no obvious inflammation in AAV-IL-37 treated naïve mice, suggesting the proinflammatory effect of IL-37 in Con A treated mice resulted from the inflamed liver microenvironment. In conclusion, IL-37 aggravated liver inflammation in Con A induced hepatitis through recruiting NK cells and elevating the IFN-γ secretion of NK cells.
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