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15 July 2021
Kosuke Tanegashima,Takahiko Hara(Stem Cell Project) and colleagues published an article entitled “Identification of Functional Domains of CXCL14 Involved in High-Affinity Binding and Intracellular Transport of CpG DNA” in Journal of Immunology.

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Elucidation of the mechanism how chemokines/DNA complex activates innate immunity

Stem cell project in our institute revealed the mechanism of activation of innate immunity by chemokine/DNA complex. This work was done by collaboration with the University of Tokushima. We published it in the American scientific journal.

<Title of the paper>
Identification of Functional Domains of CXCL14 Involved in High-Affinity Binding and Intracellular Transport of CpG DNA
<Journal>
Journal of Immunology
DOI:10.4049/jimmunol.2100030
URL: https://www.jimmunol.org/content/207/2/459

Research background

Chemokines (Note 1) are secretory proteins that promote cell migration and are known to contribute to inflammatory reactions by attracting leukocytes. In addition to the general function of chemokines, a study by our stem cell project in 2017 revealed that CXCL14, a type of chemokine, binds to a DNA sequence that is abundant in bacterial DNA called CpG DNA (Note 2). CXCL14/CpG DNA complex facilitates uptake into dendritic cells (Note 3), and significantly enhances the inflammatory response. As the results, we discovered a new function that induces innate immunity (Note 4). However,it remained unclear whether this function was common to chemokines and by what mechanism the uptake enhancement occurred.

Key findings

In this study, it was clarified that CXCL4, which is the same CXC type chemokine as CXCL14, has the same function as CXCL14 and enhances the activation of dendritic cells by CpG DNA. In addition, CXCL14 has both CpG DNA and a binding domain to cell surface receptors, and the CXCL14 / CpG DNA complex is incorporated into dendritic cells by the clathrin-dependent endocytosis pathway (Fig.1). In addition, the binding of CXCL14 / CpG DNA was analyzed by simulation, and it was shown that multiple amino acids on the N-terminal side and C-terminal side of CXCL14 work cooperatively to stabilize the binding (Fig. 2). These results revealed the non-classical function of chemokines to activate innate immunity by binding to CpG DNA.

Fig. 1 Mechanism of innate immune activation of CXCL14 and CpG DNA

Fig.1 Mechanism of innate immune activation of CXCL14 and CpG DNA
CXCL14 has both CpG DNA and a binding domain to the cell surface receptor. The CXCL14 / CpG DNA complex is endocytosed into dendritic cells to activate the CpG DNA receptor Toll-like receptor 9 (TLR9).

Fig. 1 Mechanism of innate immune activation of CXCL14 and CpG DNA

Fig.2 Simulation of binding mode between CpG DNA and CXCL14
Simulations revealed that the phosphate group of CpG DNA is recognized by the amino acids (R7, K8, R11) of CXCL14 on the N-terminal side and the amino acids (S57, R60) on the C-terminal side. These results suggested that the amino acids on the N-terminal side and the C-terminal side work cooperatively

Future direction

Both CXCL14 and CpG DNA are known to be associated with enhanced cancer immunity. In addition, the activation of dendritic cells by CXCL14 and CpG DNA shown in this study is expected to function as a vaccine adjuvant that enhances the efficacy of the vaccine. If the cooperative action of CXCL14 and CpG DNA is further elucidated using the results based on this research, it may lead to the development of more efficient cancer immunotherapeutic agents and vaccine adjuvants.

<Glossary>

(Note 1) Chemokine:
A basic protein with a small molecular weight (8-10 kDa) that induces leukocyte migration. More than 50 types of chemokine molecules have been reported.
(Note 2) CpG DNA:
Unmethylated DNA having a continuous sequence of cytosine and guanine. CpG sequences are often methylated in mammals, whereas unmethylated CpG sequences are abundantly found in bacteria and viruses. Unmethylated CpG DNA activates intracellular Toll-like receptors 9 to provoke various immune responses.
(Note 3) Dendritic cells:
Immune Cells that take up pathogens and present their antigens to T cells by processing the proteins. When activated, it expresses various cytokines and growth factors that enhance the immune response.
(Note 4) Innate immunity:
A mechanism that activates the immune response by recognizing molecules characteristic of pathogens. At present, it has been clarified that the activation of innate immunity triggers the activation of acquired immunity such as antibody production. In this study, we focus on the mechanism by which Toll-like receptor 9 recognizes unmethylated CpG DNA characteristic of bacteria.

<Grant-in-aid for this research>

It was supported by the Japan Society for the Promotion of Science (JSPS) Grant-in-Aid for Scientific Research.

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