Type 1 Innate Lymphoid Cells Protect Mice from Acute Liver Injury via Interferon-γ Secretion for Upregulating Bcl-xL Expression in Hepatocytes

Abstract

Although type 1 innate lymphoid cells (ILC1s) have been originally found as liver-resident ILCs, their pathophysiological role in the liver remains poorly investigated. Here, we demonstrated that carbon tetrachloride (CCl 4 ) injection into mice activated ILC1s, but not natural killer (NK) cells, in the liver. Activated ILC1s produced interferon-g (IFN-g) and protected mice from CCl 4 -induced acute liver injury. IFN-g released from activated ILC1s promoted the survival of hepatocytes through upregulation of Bcl-xL. An activating NK receptor, DNAM-1, was required for the optimal activation and IFN-g production of liver ILC1s. Extracellular adenosine triphosphate accelerated interleukin-12-driven IFN-g production by liver ILC1s. These findings suggest that ILC1s are critical for tissue protection during acute liver injury.

RETRACTED: Living with Yourself: Innate Lymphoid Cell Immunometabolism

“…ILCs are rapid producers of both proinflammatory and regulatory cytokines in response to local injury, inflammation, pathogen infection, or commensal microbiota perturbation [1,2]. Because most ILCs have been shown to be tissue-resident during homeostasis (with the exception of circulating NK cells) in almost all organs analyzed [5,14], their ability to quickly respond to tissue stress and inflammation underpins their critical role in regulating tissue homeostasis and repair during infection or injury [1,2,26]. However, persistent inflammatory signals can also lead to unrestrained activation of certain ILC populations at barrier surfaces, thereby exacerbating colitis, dermatitis, and contributing to tumorigenesis [27][28][29][30][31].…”

Conventional NK cells and tissue-resident ILC1s join forces to control liver metastasis

“…In the context of viral infection, trILC1s suppressed T cell-mediated viral control (Zhou et al, 2019) and were protective against acute liver injury (Nabekura et al, 2020), suggesting a regulatory rather than effector function. Using genetically modified mice that lack cNKs or trILC1s, we discovered that both innate subsets collaborated in a non-redundant fashion to control hepatic metastasis.…”

“…However, trILC1s express more inhibitory receptors (Peng et al, 2013;Sojka et al, 2014), suggesting they perform immune-regulatory functions. Nevertheless, the main roles ascribed to trILC1s so far include immune responses against haptens and early protection against viral antigens and acute liver injury (Nabekura et al, 2020;Peng et al, 2013;Weizman et al, 2017).…”

Innate lymphocytes: pathogenesis and therapeutic targets of liver diseases and cancer

“…Liver injury induced by toxins Liver ILC1s are optimally activated to produce IFN-γ, dependent on the activating receptor DNAM-1 and cytokine IL-7, after carbon tetrachloride (CCl 4 ) injection, which promotes hepatocyte survival by upregulating the expression of Bcl-xL and suppressing CCl 4induced acute liver injury. 153 During CCl 4 -induced acute liver injury, the elevated concentration of extracellular ATP was found to upregulate IL-12 production in the CD11b − DC subset and to subsequently accelerate IFN-γ secretion from hepatic ILC1s, particularly CD25 + ILC1s via ATP-P2RX7 signaling. Notably, extracellular ATP alone could not induce the production of IFN-γ in hepatic ILC1s.…”