Depiction of the pro-inflammatory and anti-inflammatory processes involved in the maintenance of a homeostatic environment in the liver. (A) Promotion of a tolerogenic and immunoregulatory hepatic environment. Hepatocytes, HSCs, LSECs, and cholangiocytes express PRRs to detect PAMPs and DAMPs in the liver, which in turn promote the up-regulation and release of immunomodulatory molecules, in addition to promoting the expression of PD-L1, and the release of IL-10 and PGE2 from innate immune cells (KCs and DCs). The immunoregulatory environment induces ILCs, T cells, and NKT cells to adopt a tolerogenic phenotype to further promote an anti-inflammatory environment. (B) Promotion of hepatic inflammation. Injured parenchymal cells secrete DAMPs and alarmins that contribute to the recruitment of circulating immune cells. DAMPs can trigger TLR9 and the NLRP3 inflammasome complex in hepatic macrophages to induce a pro-inflammatory response. Infiltrating monocytes further promote the inflammatory environment and secrete inflammatory cytokines like TNF, IL-1β, and IL-18. Recruited neutrophils secrete cytotoxic reactive oxygen and nitrogen species, IL-1β and TNF. The IL-12- and IL-18-rich environment contributes to the activation of NK cells, which ultimately promotes the production of IFN-γ and perforin. A pro-inflammatory environment within the liver can lead to PD-L1 suppression and the subsequent shift of T cells towards a Th1 response. Abbreviations: CRIg, complement receptor of the immunoglobulin superfamily; CTL, cytotoxic lymphocyte; DAMP, danger-associated molecular pattern; HMGB1, high mobility group box protein 1; ILC, innate lymphoid cell (type 1, 2, and 3); IL, interleukin; MARCO, macrophage receptor with collagenous structure; NKT, natural killer T cell; NLRP3, NOD-, LRR-, and pyrin domain-containing protein 3; PD-L1, programmed death-ligand 1; RNS, reactive nitrogen species; ROS, reactive oxygen species; TCR, T-cell receptor; TLR9, toll-like receptor 9.