Therapeutic modulation of the liver immune microenvironment

Abstract

Inflammation is a hallmark of progressive liver diseases such as chronic viral or immune-mediated hepatitis, alcohol-associated liver disease, and NAFLD. Preclinical and clinical studies have provided robust evidence that cytokines and related cellular stress sensors in innate and adaptive immunity orchestrate hepatic disease processes. Unresolved inflammation and liver injury result in hepatic scarring, fibrosis, and cirrhosis, which may culminate in HCC. Liver diseases are accompanied by gut dysbiosis and a bloom of pathobionts, fueling hepatic inflammation. Anti-inflammatory strategies are extensively used to treat human immune-mediated conditions beyond the liver, while evidence for immunomodulatory therapies and cell therapy–based strategies in liver diseases is only emerging. The development and establishment of novel immunomodulatory therapies for chronic liver diseases has been dampened by several clinical challenges, such as invasive monitoring of therapeutic efficacy with liver biopsy in clinical trials and risk of DILI in several studies. Such aspects prevented advancements of novel medical therapies for chronic inflammatory liver diseases. New concepts modulating the liver immune environment are studied and eagerly awaited to improve the management of chronic liver diseases in the future.

Antigen-driven CD8+T cell clonal expansion is a prominent feature of MASH in humans and mice

“…This alteration in immune homeostasis is particularly evident during cirrhosis in which immune responses in both the liver and systemically are dysregulated 44 . The removal of these inflammatory immune cells and restoration of normal immune homeostasis are major goals in the treatment of individuals with advanced liver disease 45 . However, the development and application of immune modulators in CLD is hindered by the incomplete understanding of both the functions of immune cells in the progression and resolution of disease and the complex interactions between these cell types in the liver.…”

Ambiguous Pathogenic Roles of Macrophages in Alcohol-Associated Liver Diseases

“…Given the lack of efficient therapeutic options for advanced stages of ALD, targeting macrophages should be further explored as a promising strategy. Rather than aiming at depleting hepatic macrophages, the focus at early stages should be to suppress inflammation and excessive macrophage activation by inhibiting bacterial translocation with the administration of antibiotics, which have been shown to improve steatohepatitis, and inhibit pathogen recognition receptors using TLR antagonists, 107 for example. Additionally, some novel therapeutic strategies developed for later stages of ALD include drugs that inhibit monocyte recruitment, modulate macrophage polarization towards an anti-inflammatory phenotype to promote tissue repair and reduce inflammation in ALD or regulate macrophage-mediated cytokine production.…”

MASLD: a systemic metabolic disorder with cardiovascular and malignant complications

“…40 41 Chronic liver inflammation is a major driver of liver fibrosis and further complications of MASLD, both inside and outside of the liver. 42 It is also well established that low-grade systemic inflammation, such as that observed in MASLD and many other associated diseases, may promote CVD outcomes 43 and tumourigenesis. 44 It has recently been demonstrated in a preclinical model of MASLD that small extracellular vesicles drive foam cell formation and thereby support atherogenesis and this effect was mediated by an interaction of miR-30a-3p with ABC transporter A1 (ABCA-1).…”