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The Role of Toll-Like Receptor Signaling in the Pathogenesis Of NEC
Published in David J. Hackam, Necrotizing Enterocolitis, 2021
Maame Efua S. Sampah, David J. Hackam
In the premature infant, in whom intestinal TLR4 expression remains persistently high due to ongoing development, TLR4 is activated by bacteria, resulting in significant mucosal inflammation (52). TLR4 signaling also explains, at least in part, the sequelae of NEC observed in the pulmonary and neurologic systems. Lung injury associated with NEC is particularly severe compared to the lung pathology seen in premature infants who do not develop NEC. TLR4 expression on the lung epithelium has been shown to trigger the recruitment of proinflammatory neutrophils into the lung through the up-regulation of CCL25 (53, 54). Strategies to inhibit TLR4 via the administration of aerosolized inhibitors were revealed to be novel lung protective strategies in the setting of NEC (54). Similarly, NEC-associated brain injury has been linked to TLR4-induced microglial activation in a mouse model, in which elimination of the TLR4 ligand high-mobility group box 1 (HMGB1) on the intestinal epithelium led to protection from brain injury in the NEC group (55).
Lymphocyte trafficking from inductive sites to effector sites
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
Valerie Verhasselt, William Agace, Oliver Pabst, Andrew Stagg
The best-studied example of a mucosal organ that preferentially recruits specific subsets of effector T cells from the circulation is the small intestinal mucosa. Vascular endothelial cells that line the blood vessels within the intestinal mucosa constitutively express MAdCAM-1, and efficient migration of B and T lymphocytes into the small intestinal and colonic mucosa is dependent on interactions between MAdCAM-1 and α4β7 integrin, which is expressed on a subset of circulating lymphocytes. Further specificity in effector T lymphocyte homing to the small intestinal mucosa is provided by the chemokine CCL25 which is constitutively expressed at high levels by epithelial cells of the small intestine but not other peripheral or mucosal tissues, including the colon. The CCL25 receptor CCR9 is expressed on a subset of circulating T lymphocytes that coexpress high levels of β7 integrins, and on the majority of T cells in the small intestinal mucosa. T-cell adoptive transfer studies in mice have demonstrated an important and selective role for this chemokine/chemokine receptor pair in mediating the efficient recruitment of effector T cells into the small intestinal mucosa. Thus, expression of MAdCAM-1 and CCL25 in the small intestinal mucosa induces the selective recruitment of T cells coexpressing CCR9 and α4β7 integrin from the circulating effector T-lymphocyte pool.
Controlling in and out – the future of interfering with immune cell trafficking in inflammatory bowel disease
Published in Expert Review of Clinical Immunology, 2023
Sebastian Zundler, Lisa Lou Schulze, Markus F. Neurath
Activated T cells that are destined to home into the gut do not only express α4β7 integrin, but also CCR9, whose ligand is the chemokine C–C motif chemokine ligand 25 (CCL25) [109,110]. CCL25 is primarily expressed in the small intestine and thymus. CCL25/CCR9 signaling has been associated with immune homeostasis, as well as disease and was further shown to promote integrin-mediated lymphocyte adhesion by activation of the integrins α4β7 and α4β1 [111–113]. CCL25 expression was further upregulated in the colons of patients with active UC and correlated with the inflammatory burden [114]. A clinical trial investigating the treatment of patients with UC with CCR9-targeted leukapheresis resulted in the safe and effective removal of activated monocytes and was associated with clinical improvement of those patients [115]. The CCR9-antagonist CCX282-B (vercirnon) was shown to inhibit CCR9-mediated chemotaxis in vitro and in vivo [116]. After promising results in a phase II trial suggesting that vercirnon was safe and effective in inducing clinical response and remission in patients with CD [117], a subsequent phase III trial failed to demonstrate clinical response [118]. Further phase III trials were terminated due to a lack of efficacy (NCT01318993, NCT01316939).
Emerging therapeutic targets for primary sclerosing cholangitis
Published in Expert Opinion on Orphan Drugs, 2018
Amir Kalani, James H. Tabibian, Keith D. Lindor
CCR9 is a chemokine receptor expressed on intraepithelial T lymphocytes of the small intestine, and also large intestine along with the integrin α4β7 which allows these T lymphocytes to migrate into these tissues. Once in the small intestine, CCR9 binds to CCL25 in the intestinal endothelium. It has also been noted that patients with PSC also abnormally express CCR9 and α4β7 in the liver, while healthy controls or patients with other liver disease do not[66]. Currently various different agents targeting these specific molecules are under investigation.
Dynamics and clinical significance of intestinal intraepithelial lymphocytes
Published in Immunological Medicine, 2019
IELs in the small intestine are distributed throughout the epithelium that overlies small intestinal villi. Even under homeostatic conditions, IELs actively migrate almost in the space between the epithelial layer and the basement membrane and occasionally showed transient movements in close association with epithelial cells (Figure 1) [17–19]. IEL-homing to the intestine and retention in the intestinal mucosa are critically dependent on the expression of a variety of gut-specific homing molecules (Table 1). β7 integrin and CC-chemokine receptor 9 (CCR9) have been well-known to be gut-homing receptors under homeostatic conditions [20]. In particular, the number of IELs was significantly reduced in all small intestinal segments of β7 integrin-deficient mice when compared to controls. In addition, the gut-associated lymphoid tissues (GALTs), comprising Peyer's patches and lamina propria lymphocytes of the intestine, appeared hypoplastic in β7 integrin-deficient mice [21,22]. In CCR9-deficient mice, the total numbers of IELs was diminished 2-fold in compared with wild-type mice and these decrease in IELs was mainly due to the presence of low numbers of TCRγδ+ IELs [23]. Natural IEL precursors such as CD8αα+ IELs have been reported to develop and express gut-homing receptors in the thymus [24–26]. On the other hand, induced IELs such as CD8αβ+ IELs and naive T cells generally do not express mucosal homing receptors are normally not detected within the intestinal epithelium. However, in these populations, gut-homing molecules β7 integrin and CCR9 are induced in GALTs, such as Peyer’s patches [27] and in mesenteric lymph nodes [28]. In these processes, the vitamin A metabolite, retinoic acid, is a key inducer of gut-homing-related molecules, upregulating β7 integrin and CCR9 [29]. Regarding the ligands for β7 integrin and CCR9, E-cadherin and CC-chemokine ligand 25 (CCL25) expressed in small intestinal epithelial cells, respectively [25]. The number of IEL in CCL25-deficient mice was reduced to the similar extent in CCR9-deficient mice [30].