CXCR4 engagement promotes dendritic cell survival and maturation

https://doi.org/10.1016/j.bbrc.2007.07.128Get rights and content

Abstract

It has been reported that human monocyte derived-dendritic cells (DCs) express CXCR4, responsible for chemotaxis to CXCL12. However, it remains unknown whether CXCR4 is involved in other functions of DCs. Initially, we found that CXCR4 was expressed on bone marrow-derived DCs (BMDCs). The addition of specific CXCR4 antagonist, 4-F-Benzoyl-TN14003, to the culture of mouse BMDCs decreased their number, especially the mature subset of them. The similar effect was found on the number of Langerhans cells (LCs) but not keratinocytes among epidermal cell suspensions. Since LCs are incapable of proliferating in vitro, these results indicate that CXCR4 engagement is important for not only maturation but also survival of DCs. Consistently, the dinitrobenzene sulfonic acid-induced, antigen-specific in vitro proliferation of previously sensitized lymph node cells was enhanced by CXCL12, and suppressed by CXCR4 antagonist. These findings suggest that CXCL12–CXCR4 engagement enhances DC maturation and survival to initiate acquired immune response.

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Materials and methods

Animals and reagent. Eight weeks old female C57BL/6 (B6) mice were purchased from Japan SLC (Hamamatsu, Japan) and maintained on a 12-h light/dark cycle under specific pathogen-free conditions. All protocols were approved by the Institutional Animal Care and Use Committee of the University of Occupational and Environmental Health.

For CXCR4 antagonist treatment, 4F-Benzoyl-TN14003 was used as CXCR4 antagonist [8], [9]. No toxicity of CXCR4 antagonist was observed at 5 μM as reported previously

CXCR4 expression in BMDCs and LCs

Initially, we evaluated the expression levels of CXCR4 on BMDCs by flow cytometry. BM cells were incubated in the culture medium with GM-CSF for 5 days. Significant amounts of CXCR4 were detected in the CD11c+ BMDCs, but CD11c fraction expressed CXCR4 to a much lesser degree (Fig. 1A). We then compared the expression level of LCs. Among epidermal cell suspensions, CXCR4 was expressed on MHC class II+ epidermal LCs but merely barely detected on MHC class II KCs (Fig. 1B).

Reduction of BMDC and LC numbers by CXCR4 antagonist treatment

To address whether

Discussion

It is a well accepted concept that chemokines are involved in not only chemotaxis but also other cellular events, such as survival, adhesion, proliferation, and differentiation [3]. For example, the roles of CCR7 on DCs have been well characterized in terms of maturation and differentiation [3]. On the other hand, the roles of CXCR4 on DCs remained largely unknown. Here, we showed that the numbers of BMDCs and LCs were decreased by CXCR4 antagonist in vitro. It is considered that LCs are

Acknowledgments

We thank Ms. Junko Nagai for technical assistance. The authors have no conflicting financial interests. This work was supported in part by grants from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, Takeda Research Foundation, Cosmetology Research Foundation, Ono Research Foundation, and Lydia O’Leary Memorial Foundation.

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