Liver Protection by ILC1s.

Abstract

ILC1-mediated IFNγ protects against moderate acute liver injury by promoting anti-apoptotic pathways in hepatocytes. ILC1-mediated IFNγ protects against moderate acute liver injury by promoting anti-apoptotic pathways in hepatocytes. CITATION Nabekura T, Riggan L, Hildreth AD, O’Sullivan TE, Shibuya A. Type 1 innate lymphoid cells protect mice from acute liver injury via interferon-. secretion for upregulating Bcl-xL expression in hepatocytes. Immunity. 2020;52:96-108. Innate lymphoid cells (ILCs) are tissue-resident cells that are mostly located at barrier tissues and rapidly produce cytokines in response to inflammatory challenges. They can protect against local pathogens but also participate in tissue repair. They are divided into ILC1s, ILC2s and ILC3s, based on their predominant production of cytokines analogous to those by T helper (Th)1, Th2 and Th17 cells, respectively. ILC1s and natural killer (NK) cells are abundant in the liver, are collectively known as group 1 innate ILCs and share NK receptors and interferon γ (IFNγ) production; however, unlike NK cells that are highly cytotoxic and recirculate, ILC1s are poorly cytotoxic and mostly sessile. The role of ILC1s in liver injury has not been known. Nabekura and colleagues demonstrate the protective role of ILC1s in a mouse model of carbon tetrachloride (CCl4)-mediated moderate acute liver injury and work out the mechanism of their activation and tissue protection. Injection of CCl4 into wild-type mice resulted in moderate liver injury characterized by elevated levels of alanine amino transferase (ALT) and evidence of perivascular tissue damage at 18 hours. This correlated with activation of ILC1s (NK1.1+DX5-CD200R+) that upregulated CD69 and CD25, but not NK cells (NK1.1+DX5-CD200R-) at 24 hours. ILC1 activation following CCl4 administration did not depend on the presence of adaptive immunity: it also occurred in recombination-activating gene (RAG)-deficient mice. ILC1s produced IFNγ in response to CCl4, which protected the liver from damage because genetic or antibody-mediated depletion of ILC1s (but not NK cells) and genetic elimination or blockade of IFNγ exacerbated liver injury. Similar results were found in another model of mild liver damage, low-dose acetaminophen, in RAG1-deficient mice. Using mice with genetic deletions, the authors further identified the requirement for the activating NK receptor DNAX accessory molecule-1 (DNAM-1; CD226), highly expressed on ILC1s, and its ligand CD155, in the CCL4-mediated activation of ILC1s and their production of IFNγ. Upstream from this, liver injury mediated the release of ATP, which acted on the purinergic receptor P2RX7, expressed on ILC1s but not NK cells, and promoted interleukin-12 (IL-12) production by dendritic cells. ATP enhanced the ability of IL-12 to induce IFNγ production by ILC1s. In turn, CCl4-mediated IFNγ resulted in the upregulation of the anti-apoptotic molecules Bcl-2 and Bcl-xL in hepatocytes, which did not occur in IFNγ-deficient or CD226-deficient mice. Importantly, the transfer of sorted ILC1s into Rag2-/-Il2rγ-/- mice (which lack adaptive immunity, NK cells and ILCs) protected them from CCl4-mediated liver injury, but less so if the transferred ILC1s were deficient in IFNγ. Overall, the authors demonstrate that production of IL-12 and ATP after CCl4-mediated liver injury results in a CD226-dependent activation of ILC1s, driving their production of IFNγ, which promotes pro-survival factors in hepatocytes. The role of ILCs in transplantation is not well studied, in part because selective elimination of ILCs is complex. The availability of Hobit-deficient mice that harbor a marked reduction in liver ILC1s but have normal numbers of NK cells (used by the authors in this manuscript) provides a nice opportunity to have these mice serve as liver donors to investigate the role of ILC1s in liver ischemia/reperfusion injury. In fact, ILC1s have already been suggested to mediate ischemia/reperfusion injury in the kidney. Moreover, IFNγ is a complex cytokine associated with acute rejection and tissue injury, but is also required for transplantation tolerance and tissue protection, because it can both enhance expression of the major histocompatibility complex and also upregulate the immune inhibitors programmed death ligand-1 (PDL1) and indoleamine 2,3-dioxygenase (IDO). This may have to do with the concentration of IFNγ, with low levels being tissue protective (as shown in this paper) and high levels being detrimental. Thus, the liver protection afforded by low-level IFNγ, depending on how durable this effect is, may point to a potential benefit of perfusing harvested livers, and perhaps kidneys, with IFNγ ex vivo to reduce ischemia/reperfusion injury following transplantation. Dr. Alegre is a professor in the Department of Medicine at the University of Chicago. She is also section editor of “Literature Watch.”