Over the past decades, the increase in alcohol-associated liver disease (ALD)-related morbidity and mortality has spurred efforts to understand the underlying mechanisms of ALD. Many early studies reported critical roles of Kupffer cells and Toll-like receptor 4 activation in the pathogenesis of ALD, which results in proinflammatory cytokine production and infiltration of macrophages and neutrophils.1 However, a recent study identified a large number of inflammatory cells in severe alcoholic hepatitis that included various types of lymphocytes.2 Nevertheless, the exact roles of these lymphocytes and the cytokines they produce in the development of alcohol-associated steatohepatitis are yet to be elucidated clearly. Of the numerous cytokines, interleukin (IL)-17, which is produced by CD4+ T helper 17 (Th17) cells, hepatic macrophages, and γδ T cells, stimulates inflammatory responses, including neutrophil migration, and triggers the onset of hepatic fibrosis.3, 4, 5 IL-17-producing Th17 cells differentiate from naive T cells through transforming growth factor-β1 and IL-6-mediated transcriptional regulation of RORγt, whereas hepatic macrophages and γδ T cells produce IL-17 after activation of TLR9 and TLR3 following exosomal delivery of mitochondrial DNA or mitochondrial double-stranded RNA. Aside from these cell types, innate lymphoid cells are also known to produce IL-17.6 Innate lymphoid cells belong to a family of innate immune cells and are largely equivalent to T cells, except that they do not express acquired antigen receptors, such as T and B cells.6,7 Innate lymphoid cells consist of 3 groups, where group 1 innate lymphoid cell encompasses cytotoxic natural killer (NK) cells and type 1 innate lymphoid cell (ILC1), with both cell types enriched in the healthy liver of mice at a roughly 1:1 ratio.7 Although ILC1 and NK cells share several functional properties, including cytokine production, they differ in developmental pathways and cytotoxicity.6,7 With recently growing interest in innate lymphoid cells, the roles of ILC1 and NK cells in various liver diseases, including nonalcoholic steatohepatitis and cancer, have previously been investigated.7 However, the question remains as to whether the interaction between ILC1 and NK cells is critical in ALD as well.

Cell Mol Gastroenterol Hepatol. 2022, doi: 10.1016/j.jcmgh.2022.10.012