Deciphering the key molecular and cellular events in neutrophil transmigration during acute inflammation

Abstract

Recruitment of leukocytes circulating in our blood to the sites of infection or tissue damage is the key phenomenon in the acute inflammatory response(s). Among the leukocytes, neutrophils are primarily recruited into the areas of acute inflammation. When neutrophils interact with activated endothelium of the blood vessels, they become migratory and cross the endothelial layer of the blood vessel wall in a process called as leukocyte extravasation. Identifying and understanding the gene regulation of this extravasation phenomenon is one of the key objective of biomedical research aimed at ameliorating or alleviating the symptoms of various diseases, such as rheumatoid arthritis, asthma, anaphylaxis, atherosclerosis, ulcerative colitis etc., that are exacerbated by inappropriate inflammatory stimuli. Here, we decipher and discuss the key genes implicated in the leukocyte transmigration using the acute inflammation model called as the Dextran Sulphate Sodium (DSS) induced Colitis in mice as a classic paradigm.

Keywords: Acute Inflammation; Colonic Epithelium; DSS Colitis; Extravasation; Leukocytes; Neutrophils Endothelium; Transmigration.

Figure 1

The Key Cellular Events Implicated in the Neutrophil Extravasation Model. The selectins, chemokines and integrins coordinate in capturing a circulating neutrophil to the vessel wall at the specific sites. This process usually takes within few milliseconds to seconds during the acute inflammatory process(s) triggered by invading microbes such as gram negative bacteria. Further neutrophil exposure to the apical endothelial chemokines causes the chemotaxis and triggers their potential to undergo transendothelial migration within minutes and more importantly without disrupting the integrity of the endothelial barrier surrounding the blood vessels.

Figure 2

Molecular and Cellular Events in Neutrophil Transmigration during Acute Inflammation. During the‘resting-state’, the junction between endothelial cells lining the blood vessels is closed, and this integrity is mediated by homotypic binding of VE-cadherin, PECAM-1 and JAM molecules. The VE-cadherin is linked to the cytoskeleton via β catenin, and this association is required for its adhesive activity. As it proceeds through the multi-step adhesion cascade, a neutrophil might trigger the dissociation of the VE-cadherin-β-catenin complex by degradation of the β-catenin and redistribution and/or internalization of the VE-cadherin. During transendothelial migration, the homophilic interactions (JAM-JAM and PECAM-1-PECAM-1) between opposing endothelial cells might be disrupted by the neutrophil, which would result in loosening of the junction. Engagement of PECAM-1 might provide a scaffold to ‘walk’ the cell through the junction via haptotactic migration.

Figure 3

Genespring GX11 analysis of Affymetrix Gene-Chip Expression Data from the colonic epithelium of 3% DSS-induced Colitis on Day 0, 2, 4, and 6 respectively in C57BL/6j mice. The raw Affymetrix CEL files downloaded from Gene Expression Omnibus (GSE22307) were normalized with RMA algorithm and subjected to One Way ANOVA, Tukey HSD and Bonferroni FDR(p<0.05). The resulting gene list was filtered based on 2 Fold cut-off compared with the Day 0 expression values. The differentially expressed genes were then classified and clustered based on Gene Ontology (GO) Analysis to decipher the differentially expressed genes in (A) Positive Regulation of Acute Inflammation, (B) Chemotaxis, (C) Leukocyte Adhesion, (D) Neutrophil Chemotaxis, and (E) Leukocyte Activation.

Figure 4

Leukocyte Transendothelial Migration Pathway. KEGG Pathway Analysis of Genes Implicated in the Leukocyte Transendothelial Migration (Red Stars) in the colonic endothelium of 3% DSS-induced Colitis in C57BL/6j mice.

Figure 5

Chemokine Signaling Pathway. KEGG Pathway Analysis of Genes Implicated in the Chemokine Signaling (Red Stars) in the colonic epithelial tissue of 3% DSS-induced Colitis in C57BL/6j mice.