Liver monocytes play a major role in the development of NASH (non-alcoholic steatohepatitis). In inflamed tissues, monocytes can differentiate in both macrophages and dendritic cells. In the present study, we investigated the role of moDCs (monocyte-derived inflammatory dendritic cells) in experimental steatohepatitis induced in C57BL/6 mice by feeding on a MCD (methionine/choline-deficient) diet. The evolution of steatohepatitis was characterized by an increase in hepatic CD45+/CD11b+ myeloid cells displaying the monocyte/macrophage marker F4-80+. In the early phases (4 weeks of treatment), Ly6Chigh/CD11b+/F4-80+ inflammatory macrophages predominated. However, their frequency did not grow further with the disease progression (8 weeks of treatment), when a 4-fold expansion of CD11b+/F4-80+ cells featuring the fractalkine receptor (CX3CR1) was evident. These CX3CR1+ cells were also characterized by the combined expression of inflammatory monocyte (Ly6C, CD11b) and dendritic cell (CD11c, MHCII) markers as well as by a sustained TNFα (tumour necrosis factor α) production, suggesting monocyte differentiation into inflammatory moDCs. The expansion of TNFα-producing CX3CR1+ moDCs was associated with an elevation in hepatic and circulating TNFα level and with the worsening of parenchymal injury. Hydrogen sulfide (H2S) has been shown to interfere with CX3CR1 up-regulation in monocyte-derived cells exposed to pro-inflammatory stimuli. Treating 4-week-MCD-fed mice with the H2S donor NaHS while continuing on the same diet prevented the accumulation of TNFα-producing CX3CR1+ moDCs without interfering with hepatic macrophage functions. Furthermore, NaHS reduced hepatic and circulating TNFα levels and ameliorated transaminase release and parenchymal injury. Altogether, these results show that inflammatory CX3CR1+ moDCs contributed in sustaining inflammation and liver injury during steatohepatitis progression.
CX3CR1-expressing inflammatory dendritic cells contribute to the progression of steatohepatitis
Salvatore Sutti, Irene Locatelli, Stefania Bruzzì, Aastha Jindal, Marco Vacchiano, Cristina Bozzola, Emanuele Albano; CX3CR1-expressing inflammatory dendritic cells contribute to the progression of steatohepatitis. Clin Sci (Lond) 1 November 2015; 129 (9): 797–808. doi: https://doi.org/10.1042/CS20150053
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