Blockade of CXCL12/CXCR4 Axis Ameliorates Murine Experimental Colitis

Mikami, Shuji; Nakase, Hiroshi; Yamamoto, Shuji; Takeda, Yasuhiro; Yoshino, Takayuki; Kasahara, Katushiro; Ueno, S.; Uza, Norimitsu; Oishi, Shinya; Fujii, Nobutaka; Nagasawa, Takashi; Chiba, Tsutomu

doi:10.1124/jpet.108.141085

Cited by 85 publications

(88 citation statements)

References 40 publications

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“…We studied protein expression and observed a regional expression pattern of CXCL12 protein in Crohn's disease showing marked up-regulation in areas of ulceration and erosion compared with normal colon. Very recently, CXCR4 expression was evaluated on peripheral T cells in patients with inflammatory bowel disease; CXCR4 immunofluorescence was significantly higher in patients with active ulcerative colitis compared with normal controls (60). CXCR4 expression levels of ulcerative colitis patients also correlated with disease activity, suggesting that the CXCL12-CXCR4 axis is involved in the inflammatory process in these patients.…”

Section: Discussionmentioning

confidence: 99%

“…CXCR4 expression levels of ulcerative colitis patients also correlated with disease activity, suggesting that the CXCL12-CXCR4 axis is involved in the inflammatory process in these patients. Indeed, blockade of the CXCL12-CXCR4 axis ameliorated murine experimental colitis (60). We hypothesized that, in view of the coexpression of CXCL12 and PAD in Crohn's disease and the evidence that chemokines are substrates for PAD (24,25), also crucial NH 2 -terminal arginine residues in CXCL12 might be converted by this enzyme.…”

Section: Discussionmentioning

confidence: 99%

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Citrullination of CXCL12 Differentially Reduces CXCR4 and CXCR7 Binding with Loss of Inflammatory and Anti-HIV-1 Activity via CXCR4

Struyf

Noppen

Loos

et al. 2009

The Journal of Immunology

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Posttranslational proteolytic processing of chemokines is a natural mechanism to regulate inflammation. In this study, we describe modification of the CXC chemokine stromal cell-derived factor 1α/CXCL12 by peptidylarginine deiminase (PAD) that converts arginine residues into citrulline (Cit), thereby reducing the number of positive charges. The three NH2-terminal arginines of CXCL12, Arg8, Arg12, and Arg20, were citrullinated upon incubation with PAD. The physiologic relevance of citrullination was demonstrated by showing coexpression of CXCL12 and PAD in Crohn’s disease. Three CXCL12 isoforms were synthesized for biologic characterization: CXCL12-1Cit, CXCL12-3Cit, and CXCL12-5Cit, in which Arg8, Arg8/Arg12/Arg20, or all five arginines were citrullinated, respectively. Replacement of only Arg8 caused already impaired (30-fold reduction) CXCR4 binding and signaling (calcium mobilization, phosphorylation of ERK and protein kinase B) properties. Interaction with CXCR4 was completely abolished for CXCL12-3Cit and CXCL12-5Cit. However, the CXCR7-binding capacities of CXCL12-1Cit and CXCL12-3Cit were, respectively, intact and reduced, whereas CXCL12-5Cit failed to bind CXCR7. In chemotaxis assays with lymphocytes and monocytes, CXCL12-3Cit and CXCL12-5Cit were completely devoid of activity, whereas CXCL12-1Cit, albeit at higher concentrations than CXCL12, induced migration. The antiviral potency of CXCL12-1Cit was reduced compared with CXCL12 and CXCL12-3Cit and CXCL12-5Cit (maximal dose 200 nM) could not inhibit infection of lymphocytic MT-4 cells with the HIV-1 strains NL4.3 and HE. In conclusion, modification of CXCL12 by one Cit severely impaired the CXCR4-mediated biologic effects of this chemokine and maximally citrullinated CXCL12 was inactive. Therefore, PAD is a potent physiologic down-regulator of CXCL12 function.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Citrullination of CXCL12 Differentially Reduces CXCR4 and CXCR7 Binding with Loss of Inflammatory and Anti-HIV-1 Activity via CXCR4

Struyf

Noppen

Loos

et al. 2009

The Journal of Immunology

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“…Moreover, in IBD, CXCL12 was significantly up-regulated in the inflamed compared to the non-inflamed epithelium and stronger expression of CXCL12 in intestinal tissues was observed in patients with UC than in those with CD. Thus, this expression was likely to be more specific in active UC patients than in CD patients, However, using CXCL12/GFP knock-in approach, Mikami, et al revealed that CXCL12-expressing cells were mainly observed in the perivascular sites of the normal colonic mucosa, suggesting that the CXCL12-expressing cells were morphologically considered to be pericytes (adjacent to the endothelial cell) but not epithelial cells (30). After DSS administration, gene expression of CXCL12 was strongly induced in mice with DSScolitis, which was compatible to human IBD data reported by Dotan.…”

Section: How Is Cxcl12/cxcr4 Axis Involved In the Pathophysiology Of mentioning

confidence: 99%

“…Mikami, et al investigated the role of CXCL12/CXCR4 axis in patents with IBD by analysis of CXCR4 expression on peripheral T cells (30). They demonstrated that CXCR4 expression on peripheral T cells in patients with active UC was significantly higher than that in inactive UC and controls.…”

Section: How Is Cxcl12/cxcr4 Axis Involved In the Pathophysiology Of mentioning

confidence: 99%

“…Next question is whether or not blocking of CXCL12-CXCR4 axis can be a new therapy for IBD. Mikami, et al showed that the effect of CXCR4 antagonist (TF14016) on colitis in dextran sodium sulfate (DSS) and interleukin (IL)-10 knockout (KO) models (30). Firstly, they examined CXCR4 expression on peripheral blood cells and CXCL12 expression of colonic tissue in mice with DSS-induced colitis.…”

Section: Blockade Of Cxcl12-cxcr4 Signaling As Therapeutic Target Of Ibdmentioning

confidence: 99%

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CXCL12-CXCR4 Axis in Ulcerative Colitis

Nakase¹,

Matsuura²,

Mikami³

et al. 2011

Ulcerative Colitis - Epidemiology, Pathogenesis and Complications

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miR‐126 downregulates CXCL12 expression in intestinal epithelial cells to suppress the recruitment and function of macrophages and tumorigenesis in a murine model of colitis‐associated colorectal cancer

Wei

Luo

et al. 2022

Molecular Oncology

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Inflammatory bowel disease, characterised by chronic relapsing‐remitting colitis, is a significant risk factor for colorectal cancer (CRC). Previously, we showed that miR‐126 functions as a tumour suppressor in CRC and is inversely correlated with tumour proliferation, metastasis and patient prognosis. In the current study, we documented a protective role for miR‐126 in colitis‐associated CRC (CAC) and its underlying mechanism. We detected downregulated miR‐126 expression during colorectal tumorigenesis in the mouse CAC model and in specimens from patients with CRC. The deficiency of miR‐126 in intestinal epithelial cells (IECs) exacerbated tumorigenesis in mice. We identified CXCL12 as a direct target of miR‐126 in inhibiting the development of colitis and CAC. Moreover, miR‐126 regulated the recruitment of macrophages via CXCL12 and decreased the levels of proinflammatory cytokines (IL‐6, IL‐12 and IL‐23). In addition, IL‐6 secreted by macrophages, which were regulated by cocultured transfected CRC cells, altered the proliferation and migration of colon cells. Our data suggest that miR‐126 exerts an antitumour effect on CAC by regulating the crosstalk between IECs and macrophages via CXCL12‐IL‐6 signalling. Our study contributes to the understanding of cancer progression and suggests miR‐126 as a potential therapy for CRC.

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Blockade of CXCL12/CXCR4 Axis Ameliorates Murine Experimental Colitis

Cited by 85 publications

References 40 publications

Citrullination of CXCL12 Differentially Reduces CXCR4 and CXCR7 Binding with Loss of Inflammatory and Anti-HIV-1 Activity via CXCR4

Citrullination of CXCL12 Differentially Reduces CXCR4 and CXCR7 Binding with Loss of Inflammatory and Anti-HIV-1 Activity via CXCR4

CXCL12-CXCR4 Axis in Ulcerative Colitis

miR‐126 downregulates CXCL12 expression in intestinal epithelial cells to suppress the recruitment and function of macrophages and tumorigenesis in a murine model of colitis‐associated colorectal cancer

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