Extracellular zinc suppresses microglial inflammatory shift via Zrt- and Irt-related protein 12-dependent uptake

Aratake T, Higashi Y, Shimizu T, Fukata S, Saito M (2026)

Publication Type: Journal article

Publication year: 2026

Journal

Journal of Pharmacological Sciences Japanese Pharmacological Society

Book Volume: 160

Pages Range: 29-36

Journal Issue: 1

DOI: 10.1016/j.jphs.2025.10.006

Abstract

Microglia exhibit phenotypic plasticity between anti-inflammatory M2 and pro-inflammatory M1 states, and the transition from M2 to M1 is implicated in the progression of acute brain injuries. However, the molecular mechanisms that regulate this phenotypic shift remain poorly understood. Zn2+, stored in presynaptic vesicles, is extracellularly released during pathological events, such as cerebral ischemia, and modulates microglial function. In this study, we aimed to investigate the role of extracellular Zn2+in the M2-to-M1 transition using BV2 microglial cells. Pretreatment with ZnCl2during M2 polarization significantly suppressed lipopolysaccharide-induced production of interleukin (IL)-6 and tumor necrosis factor-α following the phenotypic shift. Among the zinc transporters, Zrt- and Irt-related protein 12 (ZIP12) expression was markedly upregulated by IL-4 stimulation, and siRNA-mediated knockdown of ZIP12 abolished the Zn2+-mediated suppression of pro-inflammatory cytokine production. Furthermore, ZIP12 knockdown reduced intracellular Zn2+accumulation in IL-4-treated microglia, as revealed by FluoZin-3 fluorescence. These findings indicate that extracellular Zn2+is taken up via ZIP12 during M2 polarization and subsequently acts to suppress pro-inflammatory cytokine production, thereby restraining the shift toward an M1 phenotype.

Authors with CRIS profile

Takaaki Aratake Institut für Biochemie

Involved external institutions

Kochi Medical School / 高知大学医学部 JP Japan (JP)

How to cite

APA:

Aratake, T., Higashi, Y., Shimizu, T., Fukata, S., & Saito, M. (2026). Extracellular zinc suppresses microglial inflammatory shift via Zrt- and Irt-related protein 12-dependent uptake. Journal of Pharmacological Sciences, 160(1), 29-36. https://doi.org/10.1016/j.jphs.2025.10.006

MLA:

Aratake, Takaaki, et al. "Extracellular zinc suppresses microglial inflammatory shift via Zrt- and Irt-related protein 12-dependent uptake." Journal of Pharmacological Sciences 160.1 (2026): 29-36.

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