The Interleukin 33–T Helper 2 Cell Axis Promotes Human Liver Fibrosis

Liver fibrosis and cirrhosis have a high prevalence, can lead to fatal complications, and impose an increasing burden of morbidity and mortality.¹ Various triggers, such as danger molecules and specific cytokine profiles, can cause the transformation of resting hepatic stellate cells into myofibroblasts with excessive extracellular matrix production, which is a key event in liver fibrogenesis.² Concomitantly, hepatic and systemic immunologic deregulation is a typical hallmark of disease that can perpetuate fibrogenesis.³ These immunologic changes not only involve innate immune cells (eg, macrophages, neutrophils) and innate lymphoid cells (eg, natural killer cells) that reside in the liver, but also T and B cells that are classically termed as adaptive immunity.² Interestingly, intrahepatic cytotoxic CD8+ T cells can show an “auto-aggressive" behavior in injured liver, thereby participating in the pathogenesis, even without antigen-driven activation.⁴ CD4+ T cells, the T helper cell subtypes, can produce a variety of different cytokines, thereby modulating the hepatic immune environment.

T helper 2 (Th2) cells are physiologically involved in defense mechanisms against parasitic infections, but also contribute to chronic inflammatory diseases, such as allergy or fibrosis.⁵ Their secretion of the type 2 cytokines, interleukin (IL)4, IL5, IL9, and IL13, influences both immune cells and tissue-resident cells. Although the role of type 2 responses in eosinophil and Bcell stimulation is well studied in human allergy, their role in human fibrogenesis is less clearly defined.³ Previously, murine models of various fibrosis etiologies have shown a driver effect of type 2 immune responses in liver fibrosis,^6,7 but evidence in human disease has been limited to date.

In the current issue of Cellular and Molecular Gastroenterology and Hepatology, Reißing et al⁸ present a granular analysis of cellular interactions and soluble mediators involved in Th2 polarization in human liver fibrosis and cirrhosis. In patients with cirrhosis, the liver showed an increased proportion of Th2 cells, with spatial proximity to hepatic stellate cells and macrophages. Corresponding Th2-inducing cytokine profiles were found in both serum and liver. In vitro, IL33 was the fundamental cirrhotic liver–derived stimulus to induce a Th2 phenotype. Potential sources of IL33 in cirrhotic livers, as indicated by their increased IL33 expression, were facultative hepatic progenitor cells (oval cells), postmigratory CD14+ monocytes, and hepatic sinusoidal endothelial cells, which attracted Th2 cells in an IL33-dependent manner in vitro. In turn, Th2 cells contributed to hepatic stellate cell activation through IL13 secretion, although no direct effects of IL33 on hepatic stellate cells were found.⁸

The proposed mechanism here implicates hepatic sinusoidal endothelial cells, facultative hepatic progenitor cells, and monocytes as important sources of IL33, which serves as a chemoattractant and polarizer of Th2 populations, leading to hepatic stellate cell activation and fibrosis (Figure 1). Although the profibrotic role of the studied mediators has been determined previously in liver fibrosis, Reißing et al⁸ present a compelling analysis of the systemic and hepatic Th2 axis in human liver fibrogenesis. Potentially owing to the difficulty of modeling human disease in vitro, however, some mechanistic aspects of this work remain underexplored, in comparison with previously published murine data.

Figure 1.

Type 2 immune responses in human liver fibrosis and cirrhosis. The article by Reißing et al⁸ in this issue of Cellular and Molecular Gastroenterology and Hepatology identified IL33 as a key cytokine that promotes the recruitment and polarization of Th2 T cells in liver fibrosis and cirrhosis. These Th2 cells promote the fibrogenic activation of hepatic stellate cells via the cytokine IL13. IL13-R, interleukin 13 receptor. Figure created with Biorender.com.

Recent years have brought considerable insight into the plasticity and heterogeneity of hepatic immune cells, particularly in fibrosis and cirrhosis.² However, the role of specific mediators (eg, IL33) in vivo may be influenced by the redundancy of pleiotropic mediators.⁵ Although in the present work the main proposed function of IL33 was directed at Th2 cell recruitment and activation, the effects in a fibrotic microenvironment may implicate additional cells and mediators and be paralleled by other complementary mediators. As such, isolated IL33 ablation did not reduce liver fibrosis in a murine Schistosomiasis model, and only the combined ablation of thymic stromal lymphopoietin, IL25, and IL33 led to a reduction in type 2 responses and liver fibrosis.⁶ An interesting experimental finding in this context is that exogenous IL33 up-regulated proinflammatory cytokine production and hepatic inflammation but did not aggravate fibrosis in bile duct–ligated mice, suggesting that additional factors may contribute to fibrosis in vivo.⁷

In the human-based translational study by Reißing et al,⁸ antagonizing the Th2 effector cytokine IL13 reduced the fibrogenic properties of activated hepatic stellate cells, suggesting a therapeutic potential of this strategy. However, a clear challenge lies in identifying patient subgroups that are most likely to benefit from IL13 inhibition—and the optimal duration and time point for such an intervention (eg, early after hepatic stellate cell activation or in established cirrhosis; induction vs maintenance therapy). Given the clear unmet medical need for anti-inflammatory and antifibrotic drugs,⁹ further studies exploring the therapeutic implications of the current findings are warranted.

The present analysis by Reißing et al⁸ additionally corroborated the profibrotic effects of monocytes in liver fibrosis, identifying their IL33 secretion as a Th2 chemoattractant and driver of Th2 cell polarization. Vice versa, a recent analysis of pleural nematode infection showed that Th2 cells and their IL4 signaling orchestrate monocyte-to-macrophage conversion and are essential for their gain of tissue-resident properties.¹⁰ As such, a potential bidirectionality of the investigated pathways may constitute a future research direction that could impact the translational therapeutic potential of the present findings. Thus, further investigation of the Th2 response in fibrosis and cirrhosis may be an interesting step to unravel the fibrotic signaling network and to pave the way toward therapeutic approaches.