Roles of Zinc Signaling in the Immune System

Table 1

Zn transporters in physiology and pathophysiology.

Gene symbol	Protein name	Mutation type	Phenotype and disorder	Reference
SLC39A1	ZIP1	KO	Abnormal embryonic development	[15]
SLC39A2	ZIP2	KO	Abnormal embryonic development	[16]
SLC39A3	ZIP3	KO	Abnormal embryonic and T-cell development	[14]
SLC39A4	ZIP4	KO	Embryonic lethality	[18, 20–22, 60]
		Mutation	AE
SLC39A5	ZIP5	Mutation	Autosomal dominant nonsyndromic high myopia	[23]
SLC39A8	ZIP8	Hypomorphic mutation	Impaired multiple-organ organogenesis and hematopoiesis	[24–26, 61]
			Abnormal innate immune function
		KO	Osteoarthritis
		SNP	Schizophrenia
SLC39A10	ZIP10	KO	Abnormal early B-cell development	[27, 28]
			Impaired humoral immune response
SLC39A12	ZIP12	KO	Attenuation of pulmonary hypertension in a hypoxic atmosphere	[29]
SLC39A13	ZIP13	KO	Connective tissue dysplasia	[34, 62]
		Mutation	SCD-EDS
SLC39A14	ZIP14	KO	Growth retardation and impaired gluconeogenesis	[35–38]
			Impaired hepatocyte proliferation during liver regeneration after hepatectomy
			Decreased insulin signaling, hypertrophied adipocytes, and increased adipose cytokine production and plasma leptin
		Mutation	Parkinsonism-dystonia and neurodegeneration with hypermanganesemia in childhood
SLC30A1	ZnT1	KO	Embryonic lethality	[39, 63]
			Abnormal vulva formation
SLC30A2	ZnT2	Mutation; KO	Low Zn in milk	[40–43]
SLC30A3	ZnT3	KO	Prone to seizures; Alzheimer’s disease-like abnormalities	[45, 64]
SLC30A4	ZnT4	Mutation	Lethal milk: lm; Low Zn in milk	[46]
SLC30A5	ZnT5	KO	Growth retardation, osteopenia, hypodontia, and male-specific cardiac death	[47, 48]
			Impaired mast-cell functions
SLC30A7	ZnT7	KO	Reduced body fat accumulation	[49, 50]
			Insulin resistance, glucose intolerance, and hyperglycemia on a high-fat diet
SLC30A8	ZnT8	KO	Type 2 diabetes mellitus	[51–56]
		SNP	Type 1 and 2 diabetes mellitus
SLC30A10	ZnT10	Mutation	Parkinsonism, dystonia, hypermanganesemia, polycythemia, and chronic liver disease	[57–59]

Mice with a targeted ZIP3 deletion show lower DP thymocyte counts but increased number of CD4⁺ SP or CD8⁺ SP thymocytes under a Zn-limiting condition.
Patients with ZIP4 mutation (AE) show severe ZnD symptoms characterized by immunodeficiency with thymic atrophy and lymphopenia, and by recurrent infections. Epidermal LCs, which inhibit ICD triggered by the ATP release from epidermal keratinocytes, are significantly reduced in the lesions of AE patients, resulting in inflammatory skin manifestations. However, oral Zn supplementation allows LCs to recolonize and improve clinical symptoms in these patients.
Fetal fibroblasts from ZIP8 hypomorphic mice exhibit dysregulated Zn uptake and increased NF-κB activation due to insufficient control of IκB kinase. Consistent with this, mice given ZnD dietary intakes develop excessive inflammation to polymicrobial sepsis.
Mice with a targeted disruption of ZIP10 show impaired early B-cell development and antibody response, due to increased caspase activity and decreased CD45R PTPase activity, respectively.