NKp46+ natural killer cells attenuate metabolism‐induced hepatic fibrosis by regulating macrophage activation in mice

Abstract

Non-alcoholic steatohepatitis (NASH) affects 3–5% of the U. S. population having severe clinical complications to the development of fibrosis and end-stage liver diseases such as cirrhosis and hepatocellular carcinoma. A critical cause of NASH is chronic systemic inflammation promoted by innate immune cells such as liver macrophages (Mϕ) and natural killer (NK) cells. However, little is known about how the crosstalk between Mϕ and NK cells contributes to regulate NASH progression to fibrosis. In this report, we demonstrate that NKp46+ cells play an important role in preventing NASH progression to fibrosis by regulating M1/M2 polarization of liver Mϕ. Using a murine model of NASH, we demonstrate that DX5+NKp46+ NK cells are increased during disease and play a role in polarizing Mϕ toward M1-like phenotypes. This NK’s immunoregulatory function depends on the production of IFN-γ but not by granzyme-mediated cytolytic activity. Notably, depletion of NKp46+ cells promote the development of fibrosis with increased expression of profibrogenic genes as well as skewed M2 Mϕ phenotypes in hepatic tissues. Conclusion NK cell-derived IFN-γ may be essential for maintaining a balanced inflammatory environment that promotes tissue integrity and limiting NASH progression to fibrosis.

Hepatic NK cells attenuate fibrosis progression of non‐alcoholic steatohepatitis in dependent of CXCL10‐mediated recruitment

“…Using Nfil3 −/− mice that are deficient in conventional NK cells, we demonstrated that conventional NK cells prevented the fibrosis progression (Figure B). This finding was consistent with a previous finding that NKp46 + DX5 + NK cells limited NASH progression to fibrosis . NK cells can selectively kill activated hepatic stellate cells (HSCs) to curtail the development of fibrosis, and can also regulate fibrosis by modulating the fibrogenic properties of other immune cells resident in the liver .…”

“…In a previous study of spontaneous NASH in glycine N‐methyltransferase (GNMT) −/− mice, TRAIL‐producing NK cells actively contributed to promote a proinflammatory environment during early stages of fatty liver disease, thus suggesting that this cell compartment may contribute to the progression of NASH . Conversely, NKp46 + NK cells played an important role in preventing NASH progression to fibrosis by regulating the M1/M2 polarization of liver macrophages (M ϕ ) …”

γδ T Cells Promote Steatohepatitis by Orchestrating Innate and Adaptive Immune Programming

“…We recently showed that γδT cells direct T‐helper cell effector function in cancer by checkpoint receptor ligation . Similarly, in the presence of γδT cells, hepatic CD4 + T cells lower levels of cytokines, such as IFN‐γ, that have protective roles in SH . Accordingly, our in vitro data show that hepatic γδT cells mitigate CD4 + T cell IFN‐γ production.…”

Acetylcholine-producing NK cells attenuate CNS inflammation via modulation of infiltrating monocytes/macrophages

“…The intercellular action is critical in shaping the immune activities of NK cells (19,20,22,59), especially the activating effect of Ly6C hi monocytes toward NK cells (30). Reciprocally, activated NK cells can influence the ability of proinflammatory monocytes to regulate immunity (21,60,61). In our experiments, ChAT + NK cells reciprocally interacted with CCR2 + Ly6C hi monocytes through chemokine and cytokine secretion, thus regulating the immune functions of these cells.…”