Neutrophils as Components of Mucosal Homeostasis

Abstract

Inflammatory responses in the intestinal mucosa inevitably result in the recruitment of neutrophils (polymorphonuclear leukocytes [PMNs]). Epithelial cells that line the mucosa play an integral role in the recruitment, maintenance, and clearance of PMNs at sites of inflammation. The consequences of such PMN-epithelial interactions often determine tissue responses and, ultimately, organ function. For this reason, there is significant interest in understanding how PMNs function in the mucosa during inflammation. Recent studies have shown that PMNs play a more significant role in molding of the immune response than previously thought. Here, we review the recent literature regarding the contribution of PMNs to the development and resolution of inflammation, with an emphasis on the role of the tissue microenvironment and pathways for promoting epithelial restitution. These studies highlight the complex nature of inflammatory pathways and provide important insight into the difficulties of treating mucosal inflammation.

Keywords: ATP, adenosine triphosphatase; CGD, chronic granulomatous disease; DMOG, dimethyloxalylglycine; Epithelium; GI, gastrointestinal; HIF, hypoxia-inducible factor; Hypoxia-Inducible Factor; IBD, inflammatory bowel disease; ICAM-1, intracellular adhesion molecule-1; IL, interleukin; Inflammation; Metabolism; Microbiota; NADPH, reduced nicotinamide adenine dinucleotide phosphate; PHD, prolyl-hydroxylase; PMN, polymorphonuclear leukocyte; SIRPα, signal-regulatory protein-α.

Figure 1

Selective components of the microbiome influence PMN recruitment to the mucosa. The luminal microbiota, including segmented filamentous bacteria (SFB), provide signals (eg, IL23 production from multiple cell types) that drive the accumulation of Th17 cells in the lamina propria. In turn, Th17 cells secrete IL17, which activates the release of chemokines from epithelial cells to promote the accumulation of PMNs at tissue sites.

Figure 2

O₂consumption by transmigrating PMNs stabilizes mucosal HIF and promotes epithelial restitution. (A) Known steps of PMN transmigration. Recruitment signals liberated at inflammatory sites attract PMNs to migrate into and across the mucosa. Initial adhesion of PMNs is mediated by CD11b/18 to a currently unknown basolateral ligand. Movement of PMNs through the paracellular space is mediated by epithelial CD47 and coxsackie adenovirus receptor (CAR) binding to PMN SIRP-α and junctional adhesion molecule-L (JAM-L), respectively. Once at the apical surface, PMNs are retained in a CD11b/18-ICAM-1–dependent manner or cleared through anti-adhesive mechanisms involving epithelial CD55 and PMN CD97. (B) PMN accumulation at such sites become activated to consume large amounts of O₂ via the NADPH oxidase complex. As a result, the local tissue environment becomes deplete of molecular O₂, which promotes the stabilization of HIF within the epithelium and surrounding parenchyma. The activation of multiple HIF target genes promotes the active resolution of inflammation within the mucosa, particularly related to barrier and antimicrobial function. TJ, tight junction.