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REVIEW ARTICLE Table of Contents   
Year : 2005  |  Volume : 11  |  Issue : 2  |  Page : 63-72
Neutrophil expression and infiltration into Crohn's intestine


Department of Physiology, College of Medicine King Saud University, Riyadh, Saudi Arabia

Click here for correspondence address and email

Date of Submission25-Sep-2004
Date of Acceptance19-Feb-2005
 

   Abstract 

Crohn's disease (CD) is a chronic inflammatory bowel disease (IBD) of unknown etiology. The main pathological feature of IBD is transmural infiltration of polymorphonuclear neutrophils (PMN) and mononuclear cells associated with smooth muscle cell proliferation, accumulation of collagen, thickening and stenosis. While the etiology of Crohn's disease remains unknown, increased levels of proinflammatory cytokines, such as IL-1, IL-6, IL-8 and TNF in the inflamed bowel probably play a major role in the tissue injury and fibrosis that ensue. PMNs infiltrate into tissue in response to chemotactic signals produced by the tissue, such as a-chemokines (IL-8). Although, the initial infiltration of neutrophils is beneficial to kill foreign particles and bacteria, persistent infiltration causes tissue damage. This review shows some evidence of neutrophil expression in Crohn's bowel and the process of neutrophil infiltration into the inflamed tissue

Keywords: Crohn′s disease, neutrophil, chemokine, interleukin′8/IL-8, IBD, adhesion molecules.

How to cite this article:
Alzoghaibi MA. Neutrophil expression and infiltration into Crohn's intestine. Saudi J Gastroenterol 2005;11:63-72

How to cite this URL:
Alzoghaibi MA. Neutrophil expression and infiltration into Crohn's intestine. Saudi J Gastroenterol [serial online] 2005 [cited 2020 Jul 12];11:63-72. Available from: http://www.saudijgastro.com/text.asp?2005/11/2/63/33322


Crohn's disease is an inflammatory bowel disease of unknown etiology [1],[2],[3],[4],[5] . It is a chronic relapsing debilitating illness. The incidence in the United State and Europe ranges from 6-20 cases per 100,000 population per year and prevalence 90-300 per 100,000 population [1],[2],[3],[4],[5] . The annual incidence of the disease over the last ten years was 1.6: 100,000, however, for the last 20 years was 0.94: 100,000 at King Khalid University Hospital (KKUH) in Riyadh, Saudi Arabia [6]. Although any level of the alimentary tract may be involved, the terminal ileum and proximal colon are most frequently involved. A classical feature of CD is that diseased bowel segments are sharply demarcated from adjacent uninvolved segments of normal bowel. The disease starts as a focal mucosal ulcer, but as it becomes more established, there is inflammation of all layers of the bowel wall with development of long serpentine linear ulcers, fistulas, edema, fibrosis and hypertrophy of muscularis propria. Patients usually suffer from cachexia, anorexia, chronic diarrhea, intestinal obstruction, malnutrition, weight loss, abdominal pain, and growth failure.

The earliest histological lesion in CD is focal neutrophilic infiltration. This infiltration of polymorphonuclear neutrophils and mononuclear cells is the main pathological feature of IBD [7],[8] . Neutrophils, like other leukocytes, produce, noxious substances, such as reactive oxygen species (ROS), tumor necrosis factor alpha (TNFα), interleukin-1 (IL-1) and proteases [9],[10],[11] Neutrophils infiltrate occurs in response to chemotactic signals produced by tissues. The most potent chemotactic signals molecules are the chemokines [12],[13] , Persistent neutrophil infiltration into the intestinal stricture may be due to interleukin-8 (IL-8), a potent neutrophil chemokine produced by the stricture. Recently, elevated production of IL-8 by intestinal mucosa and smooth muscle cells was reported in CD [8],[14],[15] . Because of the physiological actions of the chemokines, including their ability to activate the leukocytes, many of the clinical and pathophysiological features of IBD might be explained by the abnormal increase of the chemotactic cytokines in the inflamed bowel. This review shows the evidence of neutrophil expression in the inflamed stricture in CD as well as the process through which the infiltration occurs. This study also gives a quick picture of neutrophil and monocyte infiltration in a normal wound healing.


   Neutrophil Infiltration into the Intestinal Stricture Top


Persistent neutrophil infiltration is the main pathological feature of CD. The high spontaneous secretion of proinflammatory cytokines, such as TNFα and IL-1β was observed in the mucosa of IBD [16],[17] The increased production of these proinflammatory cytokines may have a crucial role in the initiation of inflammation and perpetuation of a chronic immune response in IBD. There was a correlation between both TNFα and IL-1β secretion and the severity of local mucosal inflammation in IBD.

One of the important effects of TNFα and IL-1β is the ability to increase the expression of adhesion molecules, such as intracellular adhesion molecule-1 (ICAM­1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin as well as many other adhesion molecules on the surface of different cell types [18] . It is well known that ICAM-1 on the endothelial cells can interact with β2 integrins, such as CD 11 / CD18 on leukocytes. This interaction facilitates leukocyte (e.g., neutrophil) migration into the injured tissue to phagocytize the foreign particles. It was demonstrated that (32 integrins (particularly CD1lb) are responsible for cellular aggregation in Crohn's disease, and both (32 integrins and ICAM-1 are involved in leukocyte migration across epithelium [19],[20] . CDllb, also called Mac-1, is stored in intracellular vesicles and can be translocated to the cell surface upon neutrophil activation [21] . CD1 lb is found only on neutrophils, so the increase in CD1 lb-expressing leukocytes in tissue is an indication of the presence of neutrophils in that tissue. Comparative studies were done between colonic tissue obtained from patients with IBD and normal patients by using an immunohistochemical technique [22] . It was found that although no CD 1 l b-expressing leukocytes were observed in normal colonic epithelium, a highly significant amount of leukocytes stained for CD11b in tissue obtained from Crohn's patients. The colonic epithelium from Crohn's disease was also dominated by mononuclear leukocytes expressing CD 11 a, CD 11 c and ICAM-1 (a potent ligand of CD I Ib). In addition, endothelial cells from Crohn's specimens expressed ICAM-2, which is important for neutrophil adhesion. The expression of ICAM-3 on infiltrating neutrophils was found to be most evident in Crohn's specimens compared to controls [22] . The high expression of these adhesion molecules, particularly those specific for neutrophil migration (e.g., CDl lb/CD18 and ICAM­1), demonstrate the importance of neutrophils in the intestinal stricture of Crohn's patients. The expression of endothelial adhesion molecules, such as E and P selectins, which are important in the leukocyte adhesion process were most pronounced in Crohn's tissue. Furthermore, in the remission stage of IBD there was a marked decreased of these adhesion molecules [18] .

The metabolic and membrane perturbations that usually occur in neutrophils during activation and phagocytosis result in the release of various products into the extracellular space. There are many different substances produced from neutrophils that may participate in the pathogenesis of CD, the most important being, lysosomal enzymes, myeloperoxidase, and elastase. O'Morain et al observed increased concentrations of lysozyme, which hydrolyzes the muramic acid-N-acetyl-glucosamine bond found in the glycopeptide coat of bacteria, and myeloperoxidase, which converts hydrogen peroxide to a very potent free radical (hypochlorous acid), in rectal biopsies from patients with Crohn's disease compared to normal patients [23] . The elevation of these substances is a strong indication of the presence of neutrophils and their role in CD. These observations are consistent with the results of Adeyemi et al who found increased levels of elastase in IBD [24] .

It is well known that IL-8 is a potent chemokine and activator of neutrophils. It was reported that mucosal macrophages and neutrophils are the prominent producers of IL-8 in inflamed tissue obtained from IBD patients, whereas neutrophils represent the main IL-8-expressing cells at the injured site in IBD [25],[26] . Several studies have demonstrated abundant amounts of IL-8 in inflamed mucosa in CD [14],[27] . There was a strong correlation between IL-8 levels in colonic tissue obtained from Crohn's patients and the numbers of neutrophils infiltrating that site. The amount of IL-8 in the same tissue also was correlated with TNFα and IL- Iβ levels in the tissue. Smith et al showed that IL-8 increases the adhesiveness of neutrophils to human vascular endothelial cells and is capable of enhancing the transmigration of up to 90% of neutrophils within one hour [28] . Another study demonstrated that IL-8 induced the secretion of specific granules from neutrophils which contained the neutrophil adhesion molecules (CD 1 l b/CD 18) [29] . These data indicate that neutrophils will infiltrate the intestinal stricture in patients with CD as long as there is an abundance of the potent neutrophil chemokine, IL-8, produced in the inflamed tissue.


   Process of Neutrophil Infiltration Top


The movement of neutrophils from the circulation to the tissue, called extravasation, requires certain steps. These steps include rolling, activation, adhesion and then transmigration of the neutrophils into the inflamed tissue. [1],[30] In general, adhesion molecules can be divided into four molecular families: the selectins, the immunoglobulins, the integrins, and mucin­glycoproteins.

Migration of neutrophils begins when the vessel wall captures the neutrophil from the blood flow, and this is immediately followed by the rolling of the neutrophil along the vessel wall. This initial tethering between neutrophils and endothelial cells, and the rolling along the vessel wall, is due to the transmembrane glycoprotein adhesive molecules called selectins, which exist on both neutrophils and endothelial cells.

This initial adhesion is not strong enough to promote neutrophil infiltration. There are three types of selectins: leukocyte selectin (L-selectin), which is found on the neutrophil membrane, and two endothelium-bound selectins, platelet selectin (P-selectin), and endothelial cell selectin (E-selectin) [31] . The figure shows a schematic diagram of these adhesion molecules. There are also different ligands for these selectins; e.g., CD34 is the best characterized ligand for L-selectin. It is found on endothelial cells and represents one of the mucin-like glycoprotein family. P and E selectins are expressed on the endothelial cell membrane only when the cells are activated by appropriate inflammatory stimuli, such as TNFα, IL-1β or ROS [1] . Once endothelial cells are activated, P-selectin is mobilized from its intracellular store to the cell surface where it binds to P-selectin glycoprotein ligand-1 (PSGL-1) on the neutrophil. E-selectin requires gene transcription for expression, which is enhanced by inflammatory stimuli. It binds to E-selectin ligand-1 (ESL-1) on the neutrophil. P and E selectins support tethering of neutrophils and slow their rolling velocity.

Activated and bound L-selectin and PSGL-1 stimulate integrin expression in neutrophils which is the next step in inducing a strong interaction between neutrophils and endothelium with subsequent transmigration. Integrins are heterodimeric transmembrane glycoproteins found on neutrophils and they consist of a and 13 subunits. Neutrophils bind strongly to activated endothelial cells via these two integrins that have common R2 (CD 18) subunits. These two integrins are called Mac-1 (CD 11 b/CD 18) and LFA-1 (CD 11 c/CD 18). Mac-1 is the most critical CD 18-containing integrin in neutrophils [32] When neutrophils are exposed to inflammatory stimuli, they can rapidly mobilize Mac-1 to their membrane surface. The endothelial ligands for Mac-1 are the immunoglobulin molecules, which include ICAM- 1. ICAM-1 is markedly enhanced by inflammatory stimuli. Mac-1 can also bind to ICAM-2 (the LFA-1 ligand) with less affinity. Issekutz et al demonstrated that ICAM-1, ICAM-2, Mac-1 and LFA-1 play important roles in neutrophil migration across IL-1-activated endothelium [33] Platelet endothelial cell adhesion molecule­1 (PECAM-1) also plays an important role in the process of neutrophil transmigration [34] . PECAM-1 is found on neutrophils, platelets and endothelial cells. They can bind to another PECAM-1 on opposing cells. They are distributed over the endothelial cell surface and are also concentrated at the intracellular junction. IFN-γand TNFα can redistribute PECAM­1 molecules on the endothelial cell surface away from intracellular junctions. The important role of PECAM-1 in cell-cell adhesion and its localization at intracellular junctions may be important in the adhesion between adjacent endothelial cells. The redistribution of these molecules away from the intracellular junctions may play a role in neutrophil infiltration by reducing the affinity between the endothelial cells and thus facilitating the migration of the neutrophils [35] . Neutrophil transendothelial migration can be blocked by treating endothelial monolayers with an antibody to PECAM-1 [34] . Activated neutrophil PECAM-1 increases the activity of Mac-1 which may help maintain tight adhesion during transmigration and control the efflux of neutrophils into the tissue [36] . After transendothelial migration neutrophil PECAM-1 is down-regulated [37] . These data suggest a role for PECAM-1 in transendothelial migration. Although the exact role of PECAM-1 in neutrophil migration is unsettled, the preceding explanation is one of the ways PECAM-1 may be involved in transmigration.

Neutrophils are activated by two general promigratory stimuli, either nonchemotactic cytokines or chemoattractants. The activation of neutrophils results in increased adhesive avidity of Mac-1 and LFA-1 integrins, increased expression of these adhesion molecules, and promotion of firm adhesion to ICAM-1 on the endothelium. In contrast, L-selectin becomes less adhesive to L-selectin ligand [1] . Endothelial cells are also activated by the same stimuli, which leads to up-regulation of CAMs and mobilization of selectins. Several studies have shown that TNFα and IL-1β, which are not chemotactic for neutrophils, are capable of eliciting neutrophil transendothelial migration [33],[38] . These cytokines stimulate endothelial cells to produce IL-8 [39] . Smart et al showed that TNFa-induced transendothelial neutrophil migration is IL-8 dependent. There are many chemoattractant molecules that can promote neutrophil adhesion and migration, such as leukotriene B4 (LTB4), platelet activating factor (PAF), and complement protein C5a, as well as others. LTB4 is produced by different cell types, such as monocytes and neutrophils. It is capable of increasing the adhesiveness and transendothelial migration of neutrophils, but it has no significant effect on the expression of CAMs on the endothelium [40] PAF also has a role in promoting adhesive processes and may be important in mediating firm adhesion. C5a is produced from different cell types as well, and can bind to neutrophils to enhance neutrophil infiltration.

IL-8 is the most studied neutrophil chemokine, as explained previously. It is capable of inducing neutrophil migration through vascular endothelium and other epithelial cells [38] . Studies done in human umbilical vein endothelial cells showed that IL-8 induces the rapid secretion of specific granules in neutrophils containing Mac-1 and that it increases the expression of Mac­1 on the cell membrane. The same studies showed that IL-8 can promote the adhesive interaction between endothelium and neutrophils which was inhibited by antibodies to Mac-1. These data demonstrate that the increase in the adhesiveness of neutrophils stimulated by IL-8 is mediated by the Mac-1 molecule that is highly expressed on the cells [28],[29] IL-8 enhances neutrophil activation via binding to CXC chemokines receptors which results in strong adhesion followed by transmigration of the neutrophils into the inflamed tissue.

In summary, initiation of neutrophil migration begins with the interaction between L-selectins and their ligands on endothelial cells (rolling step). Activation of endothelial cells by proinflammatory cytokines, TNFα and IL-1β, increases the expression of P and E selectins on the endothelium surface where they interact with their neutrophil counterparts, PSGL-1 and ESL-1, respectively, that leads to a slow rolling velocity of the neutrophils and enhances tethering. At the same time, TNFα and IL-1 promote the production of IL-8 from endothelial cells, as well as other cell types, that results in inducing the mobilization of Mac-1 from granules to the neutrophil cell surface. Other integrin molecules are also expressed in activated neutrophils. TNFα and INF-γ redistribute PECAM-1 away from intracellular junctions, which facilitates neutrophil migration by weakening the affinity between the endothelial cells. Endothelial ligands for neutrophil integrins, such as ICAM-1 and ICAM-2, are markedly induced by exposing the endothelial monolayer to inflammatory cytokines. Increased adhesiveness between neutrophils and endothelium allows neutrophils to flatten out over the endothelial cells. Next, activated neutrophils extend pseudopods allowing them to pass through the intracellular junction. This last step is accompanied by down regulation of PECAM-1 in the neutrophils.


   Neutrophil and Monocyte Infiltration in Healing Wounds Top


Wound healing is a complex procedure that requires a highly regulated series of events including interactions between many cell types, production of different soluble factors, and growing of matrix components. Normal wound healing has four phases­hemostasis, inflammation, tissue formation, and tissue remodeling [41] . The prime goal of wound repair is to achieve hemostasis. The hemostasis phase represents the first step in wound healing. It is initiated at the moment of tissue injury when platelets interact with exposed collagen in the extracellular matrix. Once this interaction has occurred, platelet aggregation and adhesion occurs at the injured site, thus a hemostatic plug is formed. As a consequence of the interaction between platelets and collagen, various platelet factors are liberated including those that induce the aggregation response, those that initiate the coagulation cascade, and important cytokines and growth factors, such as platelet-derived growth factor (PDGF) which is needed for subsequent tissue repair.

The inflammatory phase begins after 6 hours of tissue injury. This phase has important events, such as migration of activated neutrophils, macrophages, and lymphocytes from the -circulation into the injured tissue. Neutrophils are the first leukocytes to infiltrate the injured tissue followed by monocytes [42] . Engelhardt et al reported that neutrophil infiltration into a human skin wound is extremely high during the first days, reaching a maximum level on day 1 [43] . Neutrophils are dominant in the wound site during the first days. In contrast, macrophages (activated monocytes) reached their maximum level at day 2. Chemokines selectively mediate the recruitment of neutrophils and monocytes in the affected area. IL-8 mRNA expression in the wound site is the highest on day 1 [43] and then it declines to reach its lowest level on day 4. Another neutrophil chemokine (GRO-α) is also expressed within 4 days after wounding. There is a strong correlation between the levels of IL-8. GRO-α and neutrophil infiltration. The cooperative expression of IL-8 and GRO-α in the wound site enhances neutrophil migration to the wound site because each of them stimulates the neutrophil via different receptors.

Monocytes infiltrate the injured tissue in response to chemotactic cytokines, such as MCP-1. MCP-1 is released from basal keratinocytes adjacent to the epidermis or from endothelial cells [44] . Peak levels of MCP-1 are detected 1 to 2 days after skin wounding and slowly decline thereafter to day 7 [43] ..

In summary, neutrophil infiltration into the wound site is very high at day 1 while IL-8 and GRO-α are at their maximum levels. Macrophage (activated monocytes) infiltration reaches its maximum level at day 2 while MCP-1 is extremely high and continues until day 7 [43] .

Neutrophils cleanse the wounded area of foreign bodies, bacteria, and infectious agents and are then extruded with the eschar or phagocytosed by macrophages. Activated macrophages release various growth factors and cytokines, which promote the next phases of repair. These growth factors are PDGF and vascular endothelial growth factor (V+EGF), which are important for the formation of granulation tissue. PDGF is a potent chemoattractant and mitogen for fibroblasts and macrophages. VEGF is important for the development of new blood vessels. Activated macrophages also release colony ­stimulating factor-1 (CSF-1), a cytokine necessary for survival of monocytes and macrophages, and TNFα. Transforming growth factor-α (TGFα) is another important cytokine for extracellular matrix synthesis and remodeling that is released by monocytes and macrophages. These growth factors and cytokines are important to promote the last two phases of healing, tissue formation and tissue remodeling [45] .

Crohn's disease is characterized by chronic inflammation involving a persistent migration of neutrophils into the intestinal stricture resulting in a dysregulation of the normal wound healing processes [12]. Activated neutrophils, as discussed previously, can release toxic substances, such as ROS that can cause tissue destruction, digestive enzymes that can breakdown proteins, and the potent inflammatory cytokine, TNFα, that enhances IL-8 production. Although, the initial infiltration of neutrophils is beneficial to kill foreign particles and bacteria, persistent infiltration causes tissue damage. The persistent neutrophil infiltration and the high IL-8 levels in mucosal tissue of patients with CD may prevent the expression of MCP-1 and the infiltration of monocytes needed for tissue repair and remodeling.

 
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Correspondence Address:
Mohammed Abdullah Alzoghaibi
Department of Physiology, College of Medicine, King Saud University, P 0 Box 2925, Riyadh 11461
Saudi Arabia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1319-3767.33322

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