Neutrophils and Intravascular Immunity in the Liver during Infection and Sterile Inflammation

Abstract

The liver is a target of many inflammatory pathologies of both infectious and noninfectious etiology. As key effectors of the innate immune system, neutrophils are critical for defense against microbial infections but are often the source of profound collateral damage to host tissues during disease states. In this article based on the authors' presentation at the 2011 Society of Toxicologic Pathology Annual Symposium, they review the molecular mechanisms of neutrophil recruitment to the liver in response to sepsis/endotoxemia, as well as sterile inflammation, and discuss variations in the molecular choreography of neutrophil trafficking in response to these different insults. Furthermore, the authors discuss the functional contributions of neutrophils within the liver microvasculature during severe sepsis, including their contributions to both host defense and organ damage. Given that inappropriate neutrophilic inflammation contributes to the pathogenesis of many liver diseases, a thorough understanding of the molecular mechanisms that regulate the recruitment of neutrophils to the liver, and their functions therein, may reveal new avenues for therapeutic interventions to treat inflammatory liver pathologies.

Identification of C-terminal Phosphorylation Sites of N-Formyl Peptide Receptor-1 (FPR1) in Human Blood Neutrophils

“…2, it is clear that the decline in sensitivity was saturable with an EC 50 ϭ (3.3 Ϯ 0.8) ϫ 10 Ϫ8 M fMLF, which closely approximates the low affinity (G-protein-unassociated) value of the fMLF K d to neutrophil membranes of 2.5 ϫ 10 Ϫ8 M (41). A stable minimum of binding was achieved in 10 min with a t1 ⁄ 2 of ϳ15 s. 3 Importantly, the corresponding bottom right-hand blot of Fig. 1 shows that NFPRa recognition of the 50 -65K region of the blot does not change more than 10 -15% over this fMLF concentration range.…”

“…They employ a subset of the largest family of cellular receptors, the G-protein-coupled seventransmembrane domain receptors (GPCRs), 2 to seek out and then destroy (2) microbial invaders. By responding to a wide variety of exogenous and endogenous stimulating agents, neutrophils are able to resolve infections but in the process also inflict collateral damage to the neighboring host tissues (3). The GPCRs bind chemotactic agents localized near infected tissue sites and foster the interception of neutrophil traffic in the vasculature by activating ␤ 2 -integrin adhesion receptors.…”

Platelet Interaction with Innate Immune Cells

“…Toll-like receptor 4 (TLR4)-activated platelets bind to neutrophils, sticking to the endothelium, and initiate NET formation [35]. Platelets mediate NETosis either via CD62P-PSGL-1 interactions [20,36], platelet GPIbα [37] or neutrophil lymphocyte-function-associated-antigen-1 (LFA-1) [38]. Additionally, platelet release products, like β-defensin [39], thromboxane A 2 (TXA 2 ), CXCL4, von Willebrand factor (vWF) [40] and high-mobility group box 1 protein (HMGB1) [41], trigger NET formation and increase bacterial clearance.…”

Tissue-Specific Neutrophil Recruitment into the Lung, Liver, and Kidney

“…While neutrophil recruitment in the portal and central venules of the liver shares many similarities with the classical paradigm of neutrophil recruitment in the systemic microcirculation, the recruitment mechanisms are substantially different in sinusoidal vessels [64,68]. The unique ultrastructural and molecular features of the endothelial cells in the liver sinusoidal vessels may explain the differences in neutrophil recruitment during liver inflammation [69]. The compartment between the endothelial cells and the hepatocytes is known as the Disse space (fig.…”