*Purpose: Innate lymphoid cells (ILCs), the most recently described family of lymphoid cells, play fundamental roles in tissue homeostasis and immune regulation through the activation of host-derived cytokine expression. Type 1 ILCs (ILC1) have been implicated in regulating immune-mediated inflammatory diseases, but the role of ILC1s in fatty liver disease and ischemia-reperfusion injury (IRI) is unclear.

*Methods: Mice were fed either standard chow (control) or a lard-based high fat diet (HFD) for at least 16 weeks. At 24-30 weeks, mice were further segmented into an IRI group and a non-IRI group. In the IRI group, mice underwent partial warm IRI for 45 minutes and were sacrificed 24 hours later; in the non-IRI group, mice were sacrificed as is. In all groups, livers were sectioned and processed for histology (HE). Hepatic lymphocytes were isolated and polychromatic flow cytometry (PFC) was used to define ILC1 cells (lineage- negative NK1.1⁺ T-bet⁺Eomos^–49a⁺49b^–) and conventional NK cells (cNK) (lineage- negative NK1.1⁺ T-bet⁺Eomes⁺49a^–9b⁺).

*Results: HFD mice gained significantly more body weight (averaging 50g versus 30g) and liver weight (2.7g versus 1.6g) than controls. We predicted worse hepatocellular damage due to IRI in HFD mice. This was confirmed by HE sections evaluated by Suzuki score system for congestion, necrosis, and vacuolization: HFD+IRI mice averaged 2.8 versus 1.9 in control+IRI. Next, we investigated the roles of cNK and ILC1 cells in fatty IRI via PFC. HFD+IRI mice showed a significant increase of ILC1 population and relative decrease of cNK population. Having demonstrated that ILC1 cells are the dominant innate effector cell population, we speculated that they are a major source of proinflammatory IFN-γ and TNF-α. To validate this, we restimulated hepatic lymphocytes ex vivo with IL-12, IL15, and IL-18 and found that ILC1 in HFD+IRI mice produced significantly more IFN-γ (p=0.01) and TNF-α (p=0.03) compared to control+IRI, indicating that ILC1s are major effector cells in fatty liver IRI.

*Conclusions: Here, we provide a first analysis of ILC1 and cNK in livers of HFD mice following IRI. The population of ILC1 was increased in HFD mice post IRI, which led to an increased secretion of IFN-γ and TNF-α. This could pave the way for further studies that seek to reduce fatty liver IRI via targeting ILC1s.

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