The spleen in liver cirrhosis: revisiting an old enemy with novel targets

Abstract

The spleen is a secondary lymphoid organ which can influence the progression of multiple diseases, notably liver cirrhosis. In chronic liver diseases, splenomegaly and hypersplenism can manifest following the development of portal hypertension. These splenic abnormalities correlate with and have been postulated to facilitate the progression of liver fibrosis to cirrhosis, although precise mechanisms remain poorly understood. In this review, we summarize the literature to highlight the mechanistic contributions of splenomegaly and hypersplenism to the development of liver cirrhosis, focusing on three key aspects: hepatic fibrogenesis, hepatic immune microenvironment dysregulation and liver regeneration. We conclude with a discussion of the possible therapeutic strategies for modulating splenic abnormalities, including the novel potential usage of nanomedicine in non-surgically targetting splenic disorders for the treatment of liver cirrhosis.

Keywords: Hepatic fibrogenesis; Hepatic immune microenvironment; Hypersplenism; Liver cirrhosis; Liver regeneration; Nanomedicine; Splenomegaly.

Fig. 1

Diagram of the normal spleen parenchyma (rat). Blue regions depict features within the white pulp whilst red regions depict the red pulp. The white pulp is composed of multiple lymphoid follicles. A follicle consists of a reactive germinal center (GC) surrounded by a mantle zone (MN) and marginal zone (MZ). There are arterioles (A) adjacent to or within the white pulp. Lymphoid tissues envelope the arterioles to form periarteriolar lymphoid sheath (PALS). The white pulp regions are analogous to “buds” whereas the arterioles are analogous to “branches”. The red pulp is distributed as sinuses and solid-appearing cords, which separate the white pulp

Fig. 2

Diagram of the liver and spleen crosstalk pathways during liver cirrhosis. During liver cirrhosis progression, spleen-derived immune cells and cytokines may travel into the injured liver via portal blood flow. At the same time, liver cirrhosis also contributes to portal hypertension, which leads to the congestion of the portal system and may give rise to splenomegaly and hypersplenism. The cirrhotic liver may also release chemokines, DAMPs like HMGB1, or exosomes into the circulation, which trigger the activation and/or migration of splenocytes

Fig. 3

Diagram of the potential usage of nanoparticles for splenic targeting. Coating nanoparticles with red blood cell-like membrane may be helpful for increasing nanoparticle uptake by splenic leukocytes. These nanoparticles should then be conjugated with drugs targeting specific signaling pathway activated in spleen. a Drug-conjugated nanoparticles may then be ingested by macrophages within the red pulp or marginal zone upon circulation and distribution into the spleen. b These drugs then inhibit pathologically activated signals, such as mTOR signaling, to reverse liver-injury induced splenic perturbations. WP white pulp, MZ marginal zone, RP red pulp. The immunofluorescence image is from an article by Chen K-H and the schematic diagram of mTOR signaling is from a review paper by Sukhbaatar et al. [82, 91]