Neutrophil-Epithelial Crosstalk During Intestinal Inflammation

Abstract

Neutrophils are the most abundant leukocyte population in the human circulatory system and are rapidly recruited to sites of inflammation. Neutrophils play a multifaceted role in intestinal inflammation, as they contribute to the elimination of invading pathogens. Recently, their role in epithelial restitution has been widely recognized; however, they are also associated with bystander tissue damage. The intestinal epithelium provides a physical barrier to prevent direct contact of luminal contents with subepithelial tissues, which is extremely important for the maintenance of intestinal homeostasis. Numerous studies have demonstrated that transepithelial migration of neutrophils is closely related to disease symptoms and disruption of crypt architecture in inflammatory bowel disease and experimental colitis. There has been growing interest in how neutrophils interact with the epithelium under inflammatory conditions. Most studies focus on the effects of neutrophils on intestinal epithelial cells; however, the effects of intestinal epithelial cells on neutrophils during intestinal inflammation need to be well-established. Based on these data, we have summarized recent articles on the role of neutrophil-epithelial interactions in intestinal inflammation, particularly highlighting the epithelium-derived molecular regulators that mediate neutrophil recruitment, transepithelial migration, and detachment from the epithelium, as well as the functional consequences of their crosstalk. A better understanding of these molecular events may help develop novel therapeutic targets for mitigating the deleterious effects of neutrophils in inflammatory bowel disease.

Keywords: Inflammatory Bowel Disease; Intestinal Epithelium; Neutrophil–Epithelial Interactions.

Figure 1

Epithelium-derived recruitment factors for neutrophils that enable neutrophil migration to inflammation sites. Schematic diagram outlining the recruitment signals released by inflammatory epithelial cells that attract neutrophils to migrate from blood vessels to sites of inflammation across the lamina propria. Epithelium-derived chemokines include cytokines (IL-8, IL-6, IL-33), chemokines (ENA-78/CXCL5, CXCL10, CXCL7, CCL20), lipid mediators (LTB4, HXA3), and matrix metalloproteinases (MMP-3, MMP-7). Figure created with BioRender.

Figure 2

Molecular basis and functional consequences of neutrophil–epithelial crosstalk in transepithelial migration. The initiation of the neutrophil adhesion step is mediated by CD11b/18 binding to the fucosylated proteins of the IEC basolateral membrane. The movement of neutrophils through the IEC intercellular space is regulated by neutrophil–epithelial cell (SIRP-α/CD47 and JAM-L/CAR) molecular interactions; in addition, CD47 expressed by neutrophils can promote neutrophil migration in a CD11b/18-dependent manner. Neutrophil-produced enzymes such as elastase and MMP-9 can disrupt cell junctions by cleaving E-cadherin (the core protein of adhesion junctions) and desmocore 2 (a key protein of desmosomes), respectively. Neutrophil transepithelial migration can stabilize HIF in IECs by promoting epithelial restitution through increased oxygen consumption. When neutrophils rise to the apical surface of the epithelium, their retention is regulated by the interaction of neutrophil-expressed CD11b/18 and epithelium-derived ICAM-1. In contrast, epithelial CD55 (which binds to the CD97 expressed on neutrophils) and CD44v6 are responsible for the detachment of migrating neutrophils. Neutrophils produce a large amount of ATP that is converted into Ado and adenosine by epithelial CD39 and CD73, respectively. Subsequently, adenosine binds to its receptor A2B (expressed on the apical membrane of IECs), which results in the secretion of chloride and water, CL^-/HCO3^- exchange, and IL-6 production by IECs. Figure created with BioRender