Re-Examining Neutrophil Participation in GN

Abstract

Significant advances in understanding the pathogenesis of GN have occurred in recent decades. Among those advances is the finding that both innate and adaptive immune cells contribute to the development of GN. Neutrophils were recognized as key contributors in early animal models of GN, at a time when the prevailing view considered neutrophils to function as nonspecific effector cells that die quickly after performing antimicrobial functions. However, advances over the past two decades have shown that neutrophil functions are more complex and sophisticated. Specifically, research has revealed that neutrophil survival is regulated by the inflammatory milieu and that neutrophils demonstrate plasticity, mediate microbial killing through previously unrecognized mechanisms, demonstrate transcriptional activity leading to the release of cytokines and chemokines, interact with and regulate cells of the innate and adaptive immune systems, and contribute to the resolution of inflammation. Therefore, neutrophil participation in glomerular diseases deserves re-evaluation. In this review, we describe advances in understanding classic neutrophil functions, review the expanded roles of neutrophils in innate and adaptive immune responses, and summarize current knowledge of neutrophil contributions to GN.

Keywords: glomerular disease; glomerulonephritis; immunology; neutrophil.

Figure 1.

The sequential steps of classic neutrophil recruitment from the vasculature to tissue in response to infection are shown. Sentinel cells are stimulated by PAMPs or DAMPs to release chemokines, cytokines, and lipid mediators that activate vascular endothelial cells to express selectins and chemokines. Neutrophils undergo capture and fast rolling through the interaction of selectins on endothelial cells with their ligands on neutrophils. Selectins and chemokines induce integrin-mediated slow rolling and neutrophil arrest. Neutrophils undergo integrin-mediated crawling to a site for transmigration. Transmigration at endothelial cell junctions is mediated by a number of additional adhesion molecules. Release of proteolytic enzymes allows neutrophils to enter the extravascular space. Extravascular neutrophils follow a chemoattractant gradient to the site of infection. Pathogens are attacked by phagocytosis and by release of NETs. Microbes within phagosomes are killed by a combination of granule contents and generation of ROS. Infiltrating neutrophils are eliminated by apoptosis.

Figure 2.

Three alternative methods of glomerular neutrophil recruitment are shown. “Secondary capture” involves platelets serving as a bridge between endothelial cells and neutrophils. A second method of neutrophil capture occurs by direct interaction with immune complexes through FcγRs or complement receptors. A third method involves neutrophil retention by slowing their crawling along glomerular capillaries. Increased neutrophil retention requires direct interaction between monocytes and neutrophils, production of TNFα by patrolling monocytes, and integrin expression by neutrophils.