The role of polymorphonuclear leukocyte trafficking in the perpetuation of inflammation during inflammatory bowel disease

Abstract

The inflammatory bowel diseases (IBDs; Crohn's disease, and ulcerative colitis) are chronically relapsing inflammatory disorders of the intestine and/or colon. The precise etiology of IBD remains unclear, but it is thought that a complex interplay between various factors including genetic predisposition, the host immune system, and the host response to luminal microbes play a role in disease pathogenesis. Furthermore, numerous lines of evidence have implicated the accumulation of large numbers of polymorphonuclear leukocyte (PMN) in the mucosa and epithelial crypts of the intestine as a hallmark of the active disease phase of IBD. Massive infiltration of PMNs is thought to be instrumental in the pathophysiology of IBD with the degree of PMN migration into intestinal crypts correlating with patient symptoms and mucosal injury. Specifically, migrated PMN have been implicated in the impairment of epithelial barrier function, tissue destruction through oxidative and proteolytic damage, and the perpetuation of inflammation through the release of inflammatory mediators. This review highlights the multifactorial role of PMN egress into the intestinal mucosa in the pathogenesis of IBD because it represents an important area of research with therapeutic implications for the amelioration of the symptoms associated with IBD.

Figure 1

Mucosal epithelium from patient with ulcerative colitis showing (A) PMN transepithelial infiltration and binding to the apical epithelial surface (red arrow) and (B) characteristic crypt abscess caused by luminal accumulation of migrated PMN (black arrow).

Figure 2

Sequential PMN trafficking cascade.

Figure 3

The integrins are αβ heterodimers; each subunit crosses the membrane once. Mammalian integrins form subfamilies that share common subunits that bind distinct ligands. Illustrated in color are the integrins that have been targeted for the treatment of human diseases. RGD: arginine-glycine-aspartic acid sequence found in some integrin ligands. C3bi: Complement 3b inactivated.