Activation of natural killer cells inhibits liver fibrosis: a novel strategy to treat liver fibrosis

Abstract

Liver lymphocytes are enriched in natural killer (NK) cells, which are involved in innate immune defenses against viral infection and tumor transformation in the liver. Recent evidence indicates that NK cell activation by IFN-alpha, IFN-gamma or dsRNA attenuates liver fibrosis through the direct killing of activated hepatic stellate cells (HSCs). Interestingly, NK cells do not kill quiescent or fully activated HSCs, but only early-activated HSCs, as only these cells express elevated levels of the NK cell-activating ligand retinoic acid-induced early transcript (RAE)-1 and TNF-related apoptosis-inducing ligand receptors, in addition to downregulated levels of the NK-cell inhibitory ligand, MHC-I. Inhibition of liver fibrosis by NK cells can also be achieved through production of IFN-gamma, which induces HSC cell cycle arrest and apoptosis in a STAT1-dependent manner. Clinically, it has also been observed that NK cell activity is negatively correlated with liver fibrosis in patients with chronic hepatitis C infection. Therefore, since NK cells inhibit liver fibrosis, stimulating NK activity could potentially be a novel strategy to treat liver fibrosis. Clinical studies will be required to confirm whether stimulating NK cell activity is effective and safe in treating human liver fibrosis.

NK cells from HCV-infected patients effectively induce apoptosis of activated primary human hepatic stellate cells in a TRAIL-, FasL- and NKG2D-dependent manner

“…[7][8][9][10][11][12][13][14] However, the potential role of human NK cells in hepatic fibrogenesis has remained largely unclear.…”

“…[7][8][9][10][11][12][13][14] In mouse models it was shown that NK cells can directly kill activated HSCs via a NKG2D-mediated mechanism, and are able to induce apoptosis of HSCs. [7][8][9][10][11][12][13][14] As activated HSCs are considered to critically contribute to the establishment of hepatic fibrosis via excessive production of collagen, killing of HSCs by immune cells may represent an important anti-fibrotic effect. Accordingly, in mouse studies dysregulated NK cell function has been shown to be associated with accelerated progression of liver fibrosis.…”

Immune mechanisms in alcoholic liver disease

“…Nonetheless, in the progression of ALD to cirrhosis alcohol interactions with both the innate and adaptive immune systems are likely more complex. Indeed, recent reports indicate that chronic alcohol intake can promote fibrosis by interfering with the capacity of liver NK cells to selectively control the proliferation of early activated stellate cells [22,26], whereas liver CD8 ? T-lymphocytes participate to the pro-fibrogenic activation of stellate cells [61].…”

Innate Lymphoid Cells: A Promising New Regulator in Fibrotic Diseases

“…IFN-γ has been developed as an effective antifibrotic cytokine and has shown promising results as a prospective antifibrotic therapy [33,65]. The mechanisms underlying its protective effects might include induction of fibroblast apoptosis and the potent inhibition of fibroblast proliferation and collagen accumulation under profibrotic conditions, which are likely brought about at least partially by its negative regulation of collagen synthesis [65,66]. Another mechanism by which IFN-γ may protect against fibrosis may be its inhibition of profibrotic cytokine TGF-β1 production, as indicated by both in vivo and in vitro studies [67].…”

“…Jeong et al [118] further demonstrated the antifibrotic function of NK cells through IFN-γ , as evidenced by its suppression during liver injury, which was found to be due to the increased production of TGF-β and expression of SOCS1 in intermediately activated HSCs. HSCs in the early activation stage have been demonstrated as more sensitive to killing by NK cells than the fully activated HSCs; [66,120] therefore, activation of NK cells could be a new therapeutic strategy to treat liver fibrosis.…”