CX₃CR1-expressing inflammatory dendritic cells contribute to the progression of steatohepatitis

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), Ly6C^high/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.