CX(3)CR1-expressing inflammatory dendritic cells contribute to the progression of steatohepatitis

摘要

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 (CX(3)CR1) was evident. These CX(3)CR1(+) 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 TNF alpha (tumour necrosis factor alpha) production, suggesting monocyte differentiation into inflammatory moDCs. The expansion of TNF alpha-producing CX(3)CR1(+) moDCs was associated with an elevation in hepatic and circulating TNF alpha level and with the worsening of parenchymal injury. Hydrogen sulfide (H2S) has been shown to interfere with CX(3)CR1 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 TNFa-producing CX(3)CR1(+) moDCs without interfering with hepatic macrophage functions. Furthermore, NaHS reduced hepatic and circulating TNF alpha levels and ameliorated transaminase release and parenchymal injury. Altogether, these results show that inflammatory CX(3)CR1(+) moDCs contributed in sustaining inflammation and liver injury during steatohepatitis progression.