Essential Role of Zinc and Zinc Transporters in Myeloid Cell Function and Host Defense against Infection

Abstract

Zinc is an essential micronutrient known to play a vital role in host defense against pathogens. Diets that are deficient in zinc lead to impaired immunity and delayed recovery from and worse outcomes following infection. Sustained insufficient zinc intake leads to dysregulation of the innate immune response and increases susceptibility to infection whereas zinc supplementation in at-risk populations has been shown to restore host defense and reduce pathogen-related morbidity and mortality. Upon infection, zinc deficiency leads to increased pathology due to imbalance in key signaling networks that result in excessive inflammation and collateral tissue damage. In particular, zinc impacts macrophage function, a critical front-line cell in host defense, in addition to other immune cells. Deficits in zinc adversely impact macrophage function resulting in dysregulation of phagocytosis, intracellular killing, and cytokine production. An additional work in this field has revealed a vital role for several zinc transporter proteins that are required for proper bioredistribution of zinc within mononuclear cells to achieve an optimal immune response against invading microorganisms. In this review, we will discuss the most recent developments regarding zinc's role in innate immunity and protection against pathogen invasion.

SLC39A8 gene encoding a metal ion transporter: discovery and bench to bedside

“…The intracellular nutrient Zn 2+ is pivotal in homeostasis-related signal transduction pathways, myeloid cell function and host defense against infection [90, 91], cell cycle, cell proliferation, embryonic development, and differentiation [92]. In human and mouse, there are >100 Zn-dependent enzymes [93], >2000 Zn-containing transcription factors [94], and an estimated ~2800 Zn 2+ -binding proteins—corresponding to ~10% of the human proteome [95].…”

Zinc Nutrition and Inflammation in the Aging Retina

“…Since an important function of the complement cascade is to coat self and foreign particles with C3‐proteins that serve as ligands for phagocytic receptors (opsonisation), this may reflect an attempt to clear an increased number of damaged or apoptotic cells in the aging retina, using macrophages and the complement system . It is known that deficits in zinc adversely impact macrophage function, resulting in dysregulation of phagocytosis and cytokine production, and this supports that local availability of zinc may influence levels of retinal inflammation, driven by resident immune cells. With regard to specific cellular interactions of macrophages with zinc, it has been observed, in the context of intracellular Histoplasma infection , that the pleiotropic cytokine, granulocyte macrophage‐colony stimulating factor (GM‐CSF), is capable of stimulating macrophages to upregulate expression of zinc exporters, Slc30a4 and Slc30a7, so that the zinc was shuttled away from phagosomes and into the Golgi apparatus .…”

Zinc Supplementation Prevents the Complications of COVID-19 Infection in Cancer Patients

“…Likewise, B lymphocyte development and antibody production, particularly immunoglobulin G, is compromised. Zinc deficiency adversely affects the macrophage, which a pivotal cell in many immunologic functions, which can dysregulate intracellular killing, cytokine production, and phagocytosis [21]. Patients with zinc deficiency show symptoms in the immune system such as a decline in the number of lymphocytes, especially helper T cells with an increase in cytotoxic T cells and monocyte cytotoxicity, with reduced activity of natural killer (NK) cell [22].…”