National Institute of Health

The onset and progression of rheumatoid arthritis, an autoimmune disease, is caused by high zinc concentrations in immune cells, researchers report

Researchers from Korea investigate the molecular dynamics that trigger rheumatoid arthritis (RA). In their recent study, they demonstrate that an increased influx of zinc in immune T cells, caused by an amplified expression of zinc importer protein ZIP8 on their surfaces, contributes to the onset of RA. On the brighter side, the researchers also report that controlling the cellular zinc level through modulation of ZIP8 is a promising approach for the treatment of RA.

How ZIP8 protein modulation indirectly contributes to rheumatoid arthritis

Researchers from Korea have recently reported the effect of ZIP8 protein variation on cellular zinc influx and T cell activation, which is found to be increased in rheumatoid arthritis.

Image courtesy: Sung-Gyoo Park from Seoul National University.

Original source: Jung-Ah Kang et al. in Experimental & Molecular Medicine, Springer Nature. Licensed under CC BY 4.0.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by inflammation of tissue and destruction of cartilage inside joints and subsequent erosion of bones. Though the trigger for this disease is not known, multiple studies on progression of the disease have revealed that its onset and severity are associated with the cellular response of T-cells (group of cells playing a vital role in the human immune system) including T helper (Th) 17 cells. Hence, regulation of T cell responses is a promising approach for amelioration of RA symptoms.

One of the possible methods for regulating immune cell response is inducing a change in the cellular zinc composition of T cells. Zinc is an essential trace element for normal functioning of immune response in mammals. Balanced concentration of zinc in cells is maintained by two families of transporter proteins: zinc exporter family (ZNT) and zinc importer family (ZIP). While ZNT mediates the efflux of zinc from cells, ZIP mediates the influx of zinc into cells. The ZNT family consists of 10 types of proteins (ZNT1–ZNT 10) and the ZIP family consists of 14 types of proteins (ZIP1–ZIP14). In previous studies, it was observed that expression of ZNT and ZIP varies among different types of immune cells. However, the possibility that the cell specific behavior of ZNT and ZIP and associated zinc movement within the cells may be responsible for the onset of RA have hitherto remained unexplored.

To explore this possibility, a group of researchers from Korea, led by Prof. Sung-Gyoo Park of Seoul National University, investigated the functioning of ZNT and ZIP families in immune cells in mice models of RA. The investigation revealed significantly high concentration of zinc in T cells present in joint fluid and joint tissues in RA mice models. Upon checking the activities of ZNT and ZIP proteins to analyze the increased zinc level in T cells in joint tissues, the researchers found the ZIP8 protein to be hyperactive. Almost 99.8% of T cells expressed ZIP8 on their cell surface leading to an increased influx of zinc. The results of their study, which was supported by a research grant from Korea Centers for Disease Control and Prevention (grant number 2020-ER6902-00), have recently been published in Experimental & Molecular Medicine.

Explaining the significance of their finding, Prof. Park states, “Zinc is essential for the maintenance of the immune system, which is why many people take zinc supplements. However, our study indicates that an increase in cellular zinc concentration in T cells caused by hyperactivity of zinc transporter ZIP8 protein contributes to the onset and exacerbation of RA. This led us to examine whether modulation of ZIP8 protein is able to reduce cellular zinc level and symptoms of RA.”

For this purpose, the researchers examined the role of ZIP8 in T cell receptor (TCR; proteins on T cell surface, which help identify antigens) signaling and found that ZIP8 deficiency dramatically reduced zinc influx in T cells, thereby reducing TCR signaling.  Attenuation of TCR signaling further leads to weakening of T cell activation and response. This proves that targeting transporter proteins can be an effective way of regulating zinc levels in immune cells and treating autoimmune diseases.

Prof. Park concludes by surmising, “Our complex immune system is affected by various factors, such as food, stress, and the environment. It is not entirely possible, nor recommended to treat autoimmune diseases caused by imbalance of cellular zinc solely through diet. It is necessary to understand the molecules responsible for the imbalance and target them for treatment. Hence, in our study, we examined the role of ZIP8 in the development of RA and also showed that modulating them can be an appropriate treatment option for RA. Perhaps within the next 5 to 10 years, we will be able to develop technology to modulate zinc transporter proteins and treat T cell-mediated inflammatory diseases.”

This certainly bodes well for people suffering from RA, and other autoimmune disorders, across the world.

Reference

Authors                                    Jung-Ah Kang^1,2,3, Ji-Sun Kwak^1,4, Sang-Heon Park^1,2,5, Kyu-Young Sim^1,2,5,

                                                Seul Ki Kim^1,4, Youngnim Shin^1,4, In Jung Jung^1,4, Jeong-In Yang^1,4, Jang-Soo Chun^1,2,4 and Sung-Gyoo Park^1,2,5

Title of original paper               ZIP8 exacerbates collagen-induced arthritis by increasing pathogenic T cell responses

Journal                                    Experimental & Molecular Medicine

DOI                                          10.1038/s12276-021-00591-1

Affiliations                               ¹School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea

                                                ²Cell Logistics Research Center, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea

                                                ³Infectious Disease Research Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB), 

                                                  Daejeon 34141, Republic of Korea

                                                ⁴National Creative Research Initiatives Center for Osteoarthritis Pathogenesis, Gwangju Institute of Science and Technology,

                                                  Gwangju 61005, Republic of Korea

                                                ⁵College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea

About National Institute of Health in Korea

The Korea National Institute of Health (KNIH), one of the major operating components of the Ministry of Health and Welfare, leads the nation’s medical research. Over the past seven decades, the KNIH has made unwavering efforts to enhance the public’s health and innovate biomedical research. The KNIH seeks to eradicate diseases and make people healthier. The KNIH establishes a scientific basis and evidence underlying health policy as well as provides national research infrastructures. We also promote public health research. To this end, we make efforts to enrich a health research environment by granting funds to research projects and keeping our resources, data, and facilities more open and accessible to researchers.

Website: http://www.nih.go.kr/eng/

About Professor Sung-Gyoo Park

Prof. Sung-Gyoo Park received his PhD in Molecular Biology in 2003 from the Seoul National University. Thereafter, he completed his postdoctoral training from Prof. Sankar Ghosh’s lab at the Yale University. He then tenured as a Professor in the School of Life Sciences at the Gwangju Institute of Science and Technology. Currently, he is with the Seoul National University as a Professor in the College of Pharmacy. Prof. Park’s research group is involved in development of approaches for controlling inflammatory diseases by identifying the responsible molecules. They also focus on inflammatory diseases, especially those involving central nervous system, which are caused due to infections.