Abstract
BackgroundNatural killer T (NKT) cells share phenotypic and functional properties with both conventional natural killer cells and T cells. These cells might have an important role in the pathogenesis of ulcerative colitis (UC). The interaction of chemokine ligand 25 (CCL25) with chemokine receptor 9 (CCR9) is involved in gut-specific migration of leukocytes and induces regulatory T cells (Tregs) to migrate to the intestine in chronic ileitis.Methodology/FindingsIn UC patients, NKT receptor CD161, CCL25, and CCR9 expression levels were evaluated by qRT-PCR. A murine model of oxazolone-induced colitis was induced in BALB/c mice. The mRNA levels of NK1.1, CCL25 and CCR9, and pro-inflammatory cytokines in mice were evaluated. The CCR9 expression on Type I or invariant NKT (iNKT) cells, and the iNKT cells chemotaxis are observed according to flow cytometry. NKT receptor CD161, CCL25 and CCR9 expression levels were significantly increased in UC patients. And, the mRNA expression levels of NK1.1, CCL25 and CCR9 were increased in oxazolone-induced colitis in mice. The production of pro-inflammatory cytokines was significantly increased, especially interleukin 4 (IL-4), IL-10 and IL-13. We observed significantly increased CCR9 expression on iNKT cells. Furthermore, we found an increased iNKT population and enhanced chemotaxis during oxazolone-induced colitis.Conclusions/SignificanceOur study suggests that CCL25/CCR9 interactions may promote the induction and function of iNKT cells during oxazolone-induced colitis. These findings may have important implications for UC treatment and suggest a role for CCR9 inhibitors.
Highlights
Ulcerative colitis (UC) and Crohn’s disease (CD) are clinical subtypes of inflammatory bowel disease (IBD) and are chronic, relapsing immune-mediated disorders of the gastrointestinal tract with unknown etiology [1]
The level of chemokine receptor 9 (CCR9) mRNA expression was significantly positively correlated with the levels of CCL25 mRNA expression (r = 0.528, p = 0.008) in all of the colonic biopsy specimens tested. These results showed that CD161, CCL25 and CCR9 expression levels were remarkably increased in ulcerative colitis (UC) patients and suggest that CCL25/CCR9 interactions have a positive correlation with Natural killer T (NKT) cells in the pathogenesis of UC
The exact etiology of IBD is unclear, it is know that altered immunological functions can contribute to the mucosal inflammation of the intestinal tract [31]. invariant NKT (iNKT) cell development is thymus dependent, but iNKT cells are found in the liver, spleen, lymph nodes and intestines [12]. iNKT cells are an important immunoregulatory population of lymphocytes able to polarize the immune response [12]
Summary
Ulcerative colitis (UC) and Crohn’s disease (CD) are clinical subtypes of inflammatory bowel disease (IBD) and are chronic, relapsing immune-mediated disorders of the gastrointestinal tract with unknown etiology [1]. There are several murine models of mucosal inflammation that mimic human IBD, including a model of hapten-induced colitis in which oxazolone (4-ethoxymethylene-2-phenyl-2-oxazoline-5-one) is delivered intrarectally to rodents. This model is driven by the production of Th2 cytokines and reproduces many UC features [4,5]. Type I or invariant NKT (iNKT) cells are composed of an invariant TCR a-chain (Va14-Ja18 in mice and Va24-Ja18 in humans) paired with a limited set of TCR bchain. These cells are present in both human and mouse intestines [9]. The interaction of chemokine ligand 25 (CCL25) with chemokine receptor 9 (CCR9) is involved in gut-specific migration of leukocytes and induces regulatory T cells (Tregs) to migrate to the intestine in chronic ileitis
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