From the AGA Journals

Neutrophils may offer therapeutic target for Wilson’s disease

Publish date: October 11, 2023
By
Will Pass
MDedge News

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The treatment of Wilson disease relies on use of chelators (D-pencilliamine; trientine) that promote urinary copper excretion and zinc, which blocks intestinal absorption.
These drugs, which must be taken continuously, are effective but are associated with significant side effects. Another chelator, bis-choline-­tetrathiomolybdate (TTM), promotes biliary, rather than urinary copper excretion.
TTM improved neurological function in clinical trials; however, dose-dependent transaminase elevations were noted.
Thus, there is a need to identify new therapeutic approaches to reduce impact of copper toxicity in hepatocytes.
In the current issue of CMGH, Mi and colleagues utilize zebrafish and mouse models of Wilson disease to generate novel insights into the pathogenesis and molecular basis of liver injury and fibrosis caused by ATP7B mutations. In the zebrafish model, they first showed that fluorescently-labeled neutrophils accumulate in the livers of live, mutant animals, which are transparent, and thus, uniquely suited to these studies. Gene expression analyses showed that the liver neutrophils are metabolically active and sensitize hepatocytes to copper-induced injury, thus providing a therapeutic rational for neutrophil inhibition. Next, the authors confirmed these findings in the mouse model, showing specifically that the N2-neutrophil subtype predominated and correlated with the degree of liver injury. Subsequent gene expression studies in the mouse, combined with in vitro analysis of bone marrow-derived neutrophils, identified a molecular signaling pathway originating in hepatocytes that triggered N2 differentiation. This pathway, which was previously shown to drive N2 differentiation in cancer models, involves TGF-beta induced methylation (and hence repression) of a gene (SOCS3) that itself, blocks expression of STAT3, a gene that drives N2 differentiation. Importantly, liver injury and fibrosis were reduced in the mouse model by drugs that inhibit TGF-beta or DNA methylation, and hence N2 differentiation, or by directly blocking the activity of N2 neutrophils.

In summary, this new study provides novel insights into not only into the pathogenesis and potential treatment of Wilson disease, but also demonstrates how signaling pathways, such as the one involving TGFbeta-SOCS3-STAT3, are reiteratively used in a variety of pathologic contexts. Going forward, it will be important to determine whether this pharmacologically modifiable signaling pathway is activated in Wilson disease patients, and whether it impacts the pathogenesis of more common liver disorders.

Michael Pack, M.D., is professor of medicine at Perelman School of Medicine, University of Pennsylvania. He has no conflicts.


 

FROM CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY

Modulating N2-neutrophil activity could offer a new therapeutic approach to Wilson’s disease, according to a preclinical study.

Inhibiting neutrophil function via transforming growth factor (TGF-beta 1) inhibition or methylation inhibition reduced parenchymal liver fibrosis and injury while improving liver function in a mouse model of Wilson’s disease, shows new research published in Cellular and Molecular Gastroenterology and Hepatology.

Also called progressive hepatolenticular degeneration, Wilson’s disease is an inherited nervous system disorder that can occur as a result of severe liver disease. It is caused by variants in the ATP7B gene which can lead to abnormalities in copper metabolism that lead to accumulation of the heavy metal in the liver and brain, resulting in damage to both organs. Approximately 60% of patients with Wilson’s disease present with hepatic syndromes, and of those 50%-60% go on to develop liver cirrhosis.

Current treatments aim to address metal deposition, but this approach is poorly tolerated by many patients, wrote investigators who were led by Junping Shi, MD, PhD, of the Institute of Hepatology and Metabolic Diseases, The Affiliated Hospital of Hangzhou Normal University, China.

“Drug interventions (such as copper chelators and zinc salts) reduce pathologic copper deposition, but side effects can be observed in up to 40% of patients during treatment and even after years of treatment, particularly nephropathy, autoimmune conditions, and skin changes,” the investigators wrote. “Liver transplantation is an effective treatment for Wilson’s disease, particularly for patients with end-stage liver disease, but donor shortages and lifelong immunosuppression limit its use. Therefore, alternative treatments with higher specificity in Wilson’s disease patients are urgently needed.”

The present study explored the underlying metabolic abnormalities in Wilson’s disease that result in liver injury and fibrosis, and related therapeutic approaches. Based on previous studies that have shown a relationship between persistent neutrophil infiltration and chronic tissue inflammation and damage, the investigators sought to explore the role of neutrophils in Wilson’s disease, with a focus on the N2 subtype.

First, they analyzed neutrophil populations in the livers of Atp7b–/– mice and atp7b–/– zebrafish, both of which are established animal models of Wilson’s disease. Compared with the wild-type comparison animals, the livers of disease model animals showed increased neutrophil infiltration, in terms of both count and density.

In one of several related experiments, administering a neutrophil agonist in the presence of copper led to significantly greater neutrophil infiltration in mutant versus wild-type fish, as well as greater increases in lipid droplets and disorganized tissue structure, which serve as markers of disease activity.

“Collectively, these data suggested that neutrophils infiltrated the liver and accelerated liver defects in Wilson’s disease,” the investigators wrote.

Additional experiments with the mouse model showed that pharmacologic ablation of N2 neutrophils via two approaches led to reduced liver fibrosis, offering a glimpse at therapeutic potential.

These findings were further supported by experiments involving a cellular model of Wilson’s disease with isolated bone marrow neutrophils. These analyses revealed the role of the TGF1–DNMT3A/STAT3 signaling axis in neutrophil polarization, and resultant liver disease progression, in Wilson’s disease.

“Neutrophil heterogeneity shows therapeutic potential, and pharmacologic modulation of N2-neutrophil activity should be explored as an alternative therapeutic to improve liver function in Wilson’s disease,” the investigators concluded, noting that TGF-beta 1, DNMT3A, or STAT3 could all serve as rational therapeutic targets.

Beyond Wilson’s disease, the findings may offer broader value for understanding the mechanisms driving other neutrophil-related diseases, as well as possible therapeutic approaches for those conditions, the authors added.

The authors disclosed no conflicts of interest.

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