In their recent paper published in Frontiers Immunology, authors Drs. Laura Mathä and Fumio Takei demonstrate the association between allergic lung inflammation and liver immunity.

 

Group 2 Innate Lymphoid Cells (ILC2s) are a family of innate lymphocytes that express GATA3 and RORα, and can produce IL-5 and IL-13 cytokines. ILC2s are activated by IL-33 and can be found in different tissues, including the lung and liver. While these cells are known to be implicated in various diseases including allergic asthma and liver fibrosis, the exact mechanisms by which ILC2s mediate protective or inflammatory effects remains to be explored.

 

In their recent work, Drs. Laura Mathä, Fumio Takei and colleagues induced lung inflammation by intranasal injection of IL-33 or papain, a protease allergen. To follow ILC2s after activation, they generated parabiotic mice and demonstrated that following IL-33 administration, ILC2s levels increased in the spleen, liver and peripheral blood. Using congenic markers, ILC2s from both mice were shown to be expanded in the lung of the mouse receiving IL-33. They then migrated through the peripheral blood to the liver in an S1P receptor-dependent manner. Lung ILC2s phenotypically differed from those in liver, with CD103 expression remaining notably low in liver ILC2s upon activation. In addition, lung-derived liver ILC2s produced larger amount of IL-5, IL-13 and IL-6 than lung ILC2s.

 

Mathä et al. also observed a shift towards type 2 immunity in the liver upon IL-33 and papain treatment, with a significant increase in eosinophils. To confirm that this was due to ILC2s, they examined CD127 conditional knock out mice and observed only mild eosinophilia. Another effect of IL-33 treatment was the increase of fibrosis-related genes (Col1a1, Acta2, Timp1), suggesting an implication of ILC2s in the development of liver fibrosis. This inflammatory effect was observed again after repeated intranasal IL-33 injections, which led to the formation of large eosinophils clusters, the differentiation of macrophages towards M2 type and the increased expression of Col1a1 in the liver. However, pre treatment with intranasal IL-33 also mediated protective effects in the context of concanavalin A (conA)-induced hepatitis.  IL-33 treated mice were protected from weight loss and exhibited less collagen deposits and a lower expression of fibrosis-associated genes. Therefore, these findings show that effects on liver function mediated by lung-derived ILC2s are context specific.

 

Overall, this work describes the process of IL33-induced activation of lung-resident ILC2s and their migration to the liver, where they can increase fibrosis or protect from conA-induced hepatitis. This study therefore details important links between allergic lung inflammation and liver immunity, with potential applications for allergy, asthma and hepatitis.