In both steady-state and during endotoxicosis, liver sinusoidal endothelial cells (LSECs) can rapidly clear lipopolysaccharide (LPS) from the bloodstream. They are located along blood sinusoids of the liver, and establish intimate contact with circulating and tissue-resident immune cells. However, their role in regulating immune responses during LPS-induced endotoxicosis remains poorly understood. Here, we show that LSECs play a dual role in regulating inflammatory responses, acting as modulators of NK cell pro-inflammatory output and as major producers of immune cell-attracting chemokines. We demonstrate that LSECs switch their chemokine expression pattern driven by LPS and IFN-γ, resulting in the production of the myeloid-attracting chemokine CCL2 and the lymphoid-attracting chemokine CXCL10, which accumulate in the serum of LPS-challenged animals. In livers of LPS-injected mice, monocytes and Kupffer cells expressed highest amounts of the pro-inflammatory cytokine Il12a and Il18 transcripts, while NK cells expressed the highest amounts of Ifng. NK cell exposure to LSECs in vitro led to global transcriptomic changes, and primed NK cells to produce higher amounts of IFN-γ in response to IL-12 and IL-18. LSECs required exposure to IFN-γ for Cxcl10 expression, and Cxcl10 gene-deletion in endothelial cells abrogated NK cell accumulation in the liver after LPS treatment. Thus, our data indicate that LSECs occupy a unique temporal and spatial position acting as central regulators that respond to both LPS and immune-derived inflammatory signals, and fuel a positive feedback loop of immune cell attraction and activation in the inflamed liver tissue.
NK cells are innate cytotoxic lymphocytes that contribute to immune responses against stressed, transformed or infected cells. The effector functions of NK cells are regulated by microenvironmental factors, including cytokines, metabolites and nutrients. Vitamin A is an essential micronutrient that plays an indispensable role in embryogenesis and development, but was also reported to regulate immune responses. However, the role of vitamin A in regulating NK cell functions remains poorly understood. Here, we show that the most prevalent vitamin A metabolite, all-trans retinoic acid (atRA), induces transcriptional and functional changes in NK cells leading to altered metabolism and reduced IFN-γ production in response to a wide range of stimuli. atRA-exposed NK cells displayed a reduced ability to support dendritic cell (DC) maturation and were inefficient in eliminating immature DCs. Moreover, they supported the polarization and proliferation of regulatory T cells. These results imply that in vitamin A-enriched environments, NK cells can acquire regulatory-like functions and might support tolerogenic immunity and/or immunosuppression.
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