Blood-Stage Plasmodium Berghei ANKA Infection Promotes Hepatic Fibrosis by Enhancing Hedgehog Signaling in Mice

Abstract

Background/Aims: Malaria is the most deadly parasitic infection in the world, resulting in damage to various organs, including the liver, of the infected organism; however, the mechanism causing this damage in the liver remains unclear. Liver fibrosis, a major characteristic of liver diseases, occurs in response to liver injury and is regulated by a complex network of signaling pathways. Hedgehog (Hh) signaling orchestrates a number of hepatic responses including hepatic fibrogenesis. Therefore, we investigated whether Hh signaling influenced the liver’s response to malarial infection. Methods: Eight-week-old male C57BL/6 mice inoculated with blood containing Plasmodium berghei ANKA (PbA)-infected erythrocytes were sacrificed when the level of parasitemia in the blood reached 10% or 30%, and the livers were collected for biochemical analysis. Liver responses to PbA infection were examined by hematoxylin and eosin staining, real-time polymerase chain reaction, immunohistochemistry and western blot. Results: Severe hepatic injury, such as ballooned hepatocytes, sinusoidal dilatation, and infiltrated leukocytes, was evident in the livers of the malaria-infected mice. Hypoxia was also induced in 30% parasitemia group. With the accumulation of Kupffer cells, inflammation markers, TNF-α, interleukin-1β, and chemokine (C-X-C motif) ligand 1, were significantly upregulated in the infected group compared with the control group. Expression of fibrotic markers, including transforming growth factor-β, α-smooth muscle actin (α-SMA), collagen 1a1, thymosin β4, and vimentin, were significantly higher in the infected groups than in the control group. With increased collagen deposition, hepatic stellate cells expressing α-SMA accumulated in the liver of the PbA-infected mice, whereas those cells were rarely detected in the livers of the control mice. The levels of Hh signaling and Yes-associated protein (YAP), two key regulators for hepatic fibrogenesis, were significantly elevated in the infected groups compared with the control group. Treatment of mice with Hh inhibitor, GDC-0449, reduced hepatic inflammation and fibrogenesis with Hh suppression in PbA-infected mice. Conclusion: Our results demonstrate that HSCs are activated in and Hh and YAP signaling are associated with this process, contributing to increased hepatic fibrosis in malaria-infected livers.

Protective Effects of Gymnema inodorum Leaf Extract on Plasmodium berghei-Induced Hypoglycemia, Dyslipidemia, Liver Damage, and Acute Kidney Injury in Experimental Mice

“…Perturbation in hepatic glucose metabolism in murine progression of malaria has also been reported [ 25 ], and hypoglycemia was relevant to liver damage [ 26 ]. Liver damage was confirmed in PbANKA-infected mice as suggested by the significant increase of liver enzymes AST, ALT, and ALP, consistent with previous studies [ 27 ]. Several studies suggested that parasitized erythrocyte sequestration contributed to liver obstruction of blood flow followed by hypoxia and excessive hemolysis, causing increased oxidative stress and leukocyte infiltration [ 28 ].…”

Astrocyte-Derived TGFβ1 Facilitates Blood–Brain Barrier Function via Non-Canonical Hedgehog Signaling in Brain Microvascular Endothelial Cells

“…Besides, the cascade is also involved in certain infectious diseases, such as malaria. The plasmodium could activate hedgehog signaling in hepatic stellate cells to induce hepatic fibrogenesis and severe hepatic inflammation [49]. In this study, we demonstrated that TGFβ1 activated the hedgehog signaling in endothelial cells through Smad2/3 regulation of Gli1/2, which enhances the TJs and promotes the endothelial barrier function.…”

Malaria infection promotes a selective expression of kinin receptors in murine liver

“…Malaria infection triggers hypertrophy of Kupffer cells, swelling of hepatocytes, sinusoidal cell necrosis and loss of hepatocyte microvilli [15, 16]. Kim et al using a murine malaria model to investigate pathological mechanisms of liver injury showed the elevation of fibrogenesis related to hepatic stellate cells signalling activation [17].…”