Innate immune cells in liver inflammation. During an infectious insult in the liver (1) resident macrophages, Kupffer cells, are the first immune cells to detect the presence of invading pathogens (bacteria, parasites, viruses, damaged, and/or necrotic cells) via PRRs/PAMPs. (2) Upon activation Kupffer cells release cytokines TNF, IL-1, and IL-6 as well as chemokines CXCL 1–3, CXCL-8, CCL-2–4 that initiate (3) the acute-phase response and inflammation. Acute inflammation is characterized by the rise in plasma proteins, collectively named acute-phase proteins (APPs) that include C-reactive protein (CRP) and complement components. (4) Proinflammatory cytokines released from activated Kupffer cells can activate hepatic sinusoidal endothelial cells to upregulate adhesion molecules (ICAM1 and 2, VCAM-1, MAdCAM etc.) and in combination with the chemokines secreted from Kupffer cells can stimulate the recruitment of neutrophils and monocytes to the liver. (5) Neutrophils are the initial phagocytes to arrive at the site of microbial invasion, where (6) they change their phenotype, they become activated and release powerful and cytotoxic antimicrobial molecules such as reactive oxygen species (ROS), oxidants, defensins, as well as chemokines to attract more neutrophils and monocytes. (7) Following their recruitment to the tissue, monocytes undergo differentiation into (8) tissue macrophages (MDMφ), which release TNF, IL-1, G-CSF, and GM-CSF factors that can extend the lifespan of neutrophils thus sustaining their presence at the site of inflammation. (9) In order for inflammation to be resolved, the dangerous neutrophils at the inflammatory loci undergo apoptosis and terminate the inflammatory process quickly. Apoptotic neutrophils represent an important anti-inflammatory stimulus to other cells involved in the resolution of inflammation by producing “eat-me” signals recognised by the surrounding phagocytes. Phosphatidylserine (PS) residues on the apoptotic neutrophil membrane allow recognition by its receptor on macrophages, which not only initiates phagocytosis but also modifies the transcriptional profile of the Mφ, increasing the production of IL-10 and TGF-b, cytokines associated with resolution of inflammatory response and tissue repair. Basophils are short-lived cells that express MHC II and CD80/CD86 costimulatory molecules, thus are able to present antigens to CD4+ T cells promoting their differentiation into Th2 cells via release of IL-4 and IL-13. Eosinophils recruited to the liver release proinflammatory mediators including granule-stored cationic proteins, cytokines, and chemokines. They also express MHC II, CD80/CD86, CD40, and ICAM-1; thus they are able to present antigens to T cells initiating or amplifying antigenic-specific immune responses.
