Mast cells play role in wound healing through the ZnT2/GPR39/IL-6 axis
Open accessAbstract
Zinc (Zn) is an essential nutrient and its deficiency causes immunodeficiency and skin disorders. Various cells including mast cells release Zn-containing granules when activated; however, the biological role of the released Zn is currently unclear. Here we report our findings that Zn transporter ZnT2 is required for the release of Zn from mast cells. In addition, we found that Zn and mast cells induce IL-6 production from inflammatory cells such as skin fibroblasts and promote wound healing, a process that involves inflammation. Zn induces the production of a variety of pro-inflammatory cytokines including IL-6 through signaling pathways mediated by the Zn receptor GPR39. Consistent with these findings, wound healing was impaired in mice lacking IL-6 or GPR39. Thus, our results show that Zn and mast cells play a critical role in wound healing through activation of the GPR39/IL-6 signaling axis.
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IL-6 transcription is induced by a variety of stimuli, such as Toll-like receptor ligands, IL-1, TNFα, reactive oxygen species and zinc, and also depends on epigenetic regulation.
“IL-6 transcription is induced by a variety of stimuli, such as Toll-like receptor (TLR) ligands, IL-1, TNFα, reactive oxygen species (ROS) and zinc (Zn) and also depends on epigenetic regulation (33, 82, 84–86).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [85]
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“To date, data have been accumulated showing that GPR39 mediates Zn-dependent signaling in keratinocytes, colonocytes, and neurons (Hershfinkel 2018).”
BackgroundInfluentialThe evolving role of mast cells in wound healing: insights from recent research and diverse models
Guth, C., Limjunyawong, N., & Pundir, P. (2024) · Immunology and Cell Biology · doi:10.1111/imcb.12824 · Cited by 19 · see citing works
“41 demonstrated that Kit W/Wv -mutant mice exhibit delayed wound healing 52 Somewhat similarly, Mas-TRECK mice express diphtheria toxin receptors under the control of a mast cell – specific enhancer which, after administration of diphtheria toxin, eliminates mast cells.”
Uchida, R., Kato, M., Hattori, Y., Kikuchi, H., Watanabe, E., Kobayashi, K., & Nishida, K. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21072472 · Cited by 20 · see citing works
“Bone marrow-derived mast cells (BMMC) were prepared as described previously [30].”
MethodSelf-citationUpdate on the multi-layered levels of zinc-mediated immune regulation.
Wessels, I., Fischer, H., & Rink, L. (2020) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2020.11.005 · Cited by 17 · see citing works
Honey-Propolis-Engineered Collagen Peptides as Promising Wound-Healing Matrix in Mouse Model
Ibrahim, H. I., Thangavelu, M., & Khalifa, A. (2022) · Molecules · doi:10.3390/molecules27207090 · Cited by 16 · see citing works
“[41], who found that mast cells played an important role in wound healing via the ZnT2/GPR39/IL-6 axis.”
BackgroundStark, K. G., Falkowski, N., Brown, C., McDonald, R., & Huffnagle, G. (2022) · Frontiers in Allergy · doi:10.3389/falgy.2022.851993 · Cited by 15 · see citing works
“In addition, there is substantial evidence for IL-6 and its interaction with mast cells not only for wound healing but also in enhancing proliferation and functionality (67, 70, 71).”
BackgroundFukuishi, N., Takahama, K., Kurosaki, H., Ono, S., & Asai, H. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26041491 · Cited by 17 · see citing works
“Additionally, mast cells enhance fibroblast infiltration and proliferation [16], whereas the zinc contained within mast cell granules promotes tissue repair and regeneration [17].”
Functions of the Zinc-Sensing Receptor GPR39 in Regulating Intestinal Health in Animals
Xia, P.-P., Yan, L., Ji, X., Wu, Y., Lian, S.-Q., & Zhu, G. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232012133 · Cited by 14 · see citing works
Signaling pathway mechanisms of neurological diseases induced by G protein‐coupled receptor 39
Cao, B., Wang, J., & Feng, J. (2023) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.14174 · Cited by 13
Utilizing mast cells in a positive manner to overcome inflammatory and allergic diseases
Zhang, Z., Ernst, P. B., Kiyono, H., & Kurashima, Y. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.937120 · Cited by 12 · see citing works
Self-citationSun, Q., Dong, X., Meng, Q., Xu, J., & Wang, T. (2024) · ACS Applied Bio Materials · doi:10.1021/acsabm.4c01196 · Cited by 10
McGourty, K., Vijayakumar, R., Wu, T., Gagnon, A., & Kelleher, S. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms231911467 · Cited by 9 · see citing works
“As these effects could result from ZnT2-mediated Paneth cell [8], mast cell [36], or colonocyte dysfunction, further studies using tissue-specific ZnT2-null mice are required to understand the function relevance of ZnT2 in each celltype in managing mucosal homeostasis and response to infectious colitis.”
BackgroundHan, Z., Sun, P., Huang, M., Tang, Y., Zhang, Z., Yu, H., Liu, J.-S., Wu, Y.-Y., He, P., Tu, Y.-Y., et al. (2025) · Materials Today Advances · doi:10.1016/j.mtadv.2025.100633 · Cited by 8
Zn2+ transients and signaling in mammalian systems.
Rakshit, A., & Palmer, A. E. (2025) · TIBS -Trends in Biochemical Sciences. Regular ed · doi:10.1016/j.tibs.2025.09.002 · Cited by 7 · see citing works
ZnTs: Key Regulators of Zn2+ Homeostasis in Diseases
Liu, H., Chen, M.-L., Duan, J., Lu, R., & Li, L. (2025) · Cell Biology International · doi:10.1002/cbin.70056 · Cited by 5 · see citing works
Orphan receptor GPR39: A potential therapeutic target for inflammatory diseases.
Ran, S., Pan, L., & Shen, Y. (2025) · Gene · doi:10.1016/j.gene.2025.149625 · Cited by 4 · see citing works
Evaluation of CONUT Score and Serum Zinc Levels in Patients with Diabetic Foot Ulcers
Nakamura, H., Makiguchi, T., Yamada, Y., Tsunoda, A., Tomaru, N., & Yokoo, S. (2025) · International Journal of Lower Extremity Wounds · doi:10.1177/15347346251326247 · Cited by 3 · see citing works
“28,29 Zinc de fi ciency has been linked to increased oxidative stress, elevated extracellular ATP, and exacerbated in fl ammation, all of which impair wound healing.”
García, E. R., Barros, E., Stransky, S., Chávez-Olórtegui, C., Freitas, M., Novaes, R., & Gonçalves, R. V. (2020) · Evidence-Based Complementary and Alternative Medicine · doi:10.1155/2020/8273986 · Cited by 3 · see citing works
“, type III) by matrix metalloproteinases and colagenogenesis (especially mediated by FGF and TGFβ), playing a direct role in the reorganization of the fibrous matrix and morphofunctional remodeling of the skin [63, 64].”
BackgroundResultZheng, L.-C., Yang, X., Cui, Y., Huo, J., Gao, Y., Peng, R.-F., Liu, B., Hu, W., Fan, Q.-C., Liu, L., et al. (2026) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2026.152215 · Cited by 1 · see citing works
Semaphorin7A-expressing mast cell exosomes promote wound healing.
Cho, K.-A., Kim, H., Choi, S., Woo, S.-Y., & Roh, J. (2025) · Experimental Cell Research · doi:10.1016/j.yexcr.2025.114771 · Cited by 1
Iovino, L., Cooper, K., Deroos, P., Kinsella, S., Evandy, C., Ugrai, T., Mazziotta, F., Ensbey, K., Granadier, D., Hopwo, K., et al. (2021) · bioRxiv · doi:10.1101/2021.09.02.458741 · Cited by 1 · see citing works
Imanishi, M., Yamakawa, Y., Fukushima, K., Ikuto, R., Maegawa, A., Izawa-Ishizawa, Y., Horinouchi, Y., Kondo, M., Kishuku, M., Goda, M., et al. (2020) · Naunyn-Schmiedeberg's Archives of Pharmacology · doi:10.1007/s00210-020-01859-5 · Cited by 1 · see citing works
The Zinc–Senescence Axis in Skin Aging and Wound Healing: A Narrative Review
Mutig, K., Singh, P. B., Azhibek, D., & Lebedeva, S. A. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27177713
“Zinc deficiency adversely affects the expression of IL-2 and IFN-γ and increases the production of the pro-inflammatory cytokines IL-1 β , IL-6, and TNF [136], which are involved in wound healing, likely through GPR39-mediated signaling pathways [15].”
InfluentialMorais, T. S., da Silva, O. C., de Queiroz, M. N., Dias, T. G., Fernandes, F. L., de Almeida, D. D., Maia, T. M. B., Reis, A. S., Dutra, R. P., Fernandes, T. A. A. D. M., et al. (2026) · ACS Omega · doi:10.1021/acsomega.6c05452
Ryguła, I., Rosiek, V., & Kos‐Kudła, B. (2026) · Cancers · doi:10.3390/cancers18142257
Improving oleoyl hyaluronan self-assembly and functional properties using zinc ions.
Sita, J., Čepa, M., Lehká, K., Pavlík, V., Kulhánek, J., Vacková, M., Žídek, O., & Ondreáš, F. (2026) · Carbohydrate Polymers · doi:10.1016/j.carbpol.2026.125203
The impact of smoking on serum zinc levels among Sudanese adults: a case-control study
Yousif, S., Merghani, T., Alawad, A. O., Satti, S., & Yousif, N. (2026) · The Pan African Medical Journal · doi:10.11604/pamj.2026.53.145.47865
“In general, zinc is involved in numerous biological processes [14,15].”
Effect of taspine hydrochloride on KGF signal pathway in skin wound healing in rats
Zhang, X.-J., & Liu, J. (2022) · Tropical Journal of Pharmaceutical Research · doi:10.4314/tjpr.v21i8.15
“The important pro-inflammatory cytokine IL-6 is required for effective healing of skin wounds [15].”
Background
- Authors
- Nishida, K., Hasegawa, A., Yamasaki, S., Uchida, R., Ohashi, W., Kurashima, Y., Kunisawa, J., Kimura, S., Iwanaga, T., Watarai, H., Hase, K., Ogura, H., Nakayama, M., Kashiwakura, J.-I., Okayama, Y., Kubo, M., Ohara, O., Kiyono, H., Koseki, H., Murakami, M., & Hirano, T.
- Affiliations
- Suzuka University of Medical Science (JP)
- Shinshu University (JP)
- RIKEN Center for Integrative Medical Sciences (JP)
- Chiba University (JP)
- National Institute of Biomedical Innovation, Health and Nutrition (JP)
- Keio University (JP)
- Hokkaido University (JP)
- Kanazawa University (JP)
- Hyogo Medical University (JP)
- Kazusa DNA Research Institute (JP)
- Nihon University (JP)
- Tokyo University of Science (JP)
- National Institutes for Quantum Science and Technology (JP)
- Corresponding author
- Nishida, Keigo
- ORCID
- Nishida, Keigo
- Hasegawa, Aiko
- Yamasaki, Satoru
- Uchida, Ryota
- Ohashi, Wakana
- Kurashima, Yosuke
- Kunisawa, Jun
- Kimura, Shunsuke
- Iwanaga, Toshihiko
- Watarai, Hiroshi
- Hase, Koji
- Ogura, Hideki
- Nakayama, Manabu
- Kashiwakura, Jun-ichi
- Okayama, Yoshimichi
- Kubo, Masato
- Ohara, Osamu
- Kiyono, Hiroshi
- Koseki, Haruhiko
- Murakami, Masaaki
- Venue
- Scientific Reports
- Published
- 2019-07-25
- Volume
- 9
- Issue
- 1
- Pages
- 10842-10842
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC6658492
- OpenAlex
- W2964146808
- Cited by
- 53
- References
- 74
- Citations by year
- 2026: 4 · 2025: 11 · 2024: 3 · 2023: 3 · 2022: 11 · 2021: 13 · 2020: 8
- FWCI
- 5.59
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Institutional Repositories DataBase (IRDB) (submittedVersion, cc-by-nc-nd)
- QST-Repository (National Institutes for Quantum and Radiological Science and Technology) (submittedVersion, cc-by-nc-nd)
- Funders
- Takeda Science Foundation (JP16K15152, JP18H05299)
- Uehara Memorial Foundation
- GlaxoSmithKline Japan
- Pharmaceutical Society of Japan
- Mochida Memorial Foundation for Medical and Pharmaceutical Research
- Chiba University
- SENSHIN Medical Research Foundation (JP18H05299, JP16K15152)
- University of California, San Diego
- Japan Society for the Promotion of Science (19K07239, 18KK0432, 20K20320, 19H03491, 19K22634, 19H03450, 16K15152, JP18H05299)
- RIKEN
- Science and Technology Research Partnership for Sustainable Development
- Topics
- Health Sciences › Medicine › Rehabilitation › Wound Healing and Treatments
- Health Sciences › Nursing › Nutrition and Dietetics › Trace Elements in Health
- Life Sciences › Immunology and Microbiology › Immunology › Mast cells and histamine
- Keywords
- mast cells, wound healing, zinc, ZnT2, GPR39, interleukin-6, zinc transporters, dermal fibroblasts, inflammation, inflammatory cytokines, zinc deficiency
- MeSH terms
- Animals, Cell Line, Cells, Cultured, Mast Cells, Wound Healing, Interleukin-6, Cation Transport Proteins, Receptors, G-Protein-Coupled, Mice
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