Metallothioneins: Emerging Modulators in Immunity and Infection

Abstract

Metallothioneins (MTs) are a family of metal-binding proteins virtually expressed in all organisms including prokaryotes, lower eukaryotes, invertebrates and mammals. These proteins regulate homeostasis of zinc (Zn) and copper (Cu), mitigate heavy metal poisoning, and alleviate superoxide stress. In recent years, MTs have emerged as an important, yet largely underappreciated, component of the immune system. Innate and adaptive immune cells regulate MTs in response to stress stimuli, cytokine signals and microbial challenge. Modulation of MTs in these cells in turn regulates metal ion release, transport and distribution, cellular redox status, enzyme function and cell signaling. While it is well established that the host strictly regulates availability of metal ions during microbial pathogenesis, we are only recently beginning to unravel the interplay between metal-regulatory pathways and immunological defenses. In this perspective, investigation of mechanisms that leverage the potential of MTs to orchestrate inflammatory responses and antimicrobial defenses has gained momentum. The purpose of this review, therefore, is to illumine the role of MTs in immune regulation. We discuss the mechanisms of MT induction and signaling in immune cells and explore the therapeutic potential of the MT-Zn axis in bolstering immune defenses against pathogens.

Stress responses, M2 macrophages, and a distinct microbial signature in fatal intestinal acute graft-versus-host disease

“…We observed that processes involved in MT-associated stress responses are increased in steroid-refractory aGVHD compared with aGVHD onset. MTs are widely expressed stress response proteins that bind heavy divalent metals and mitigate oxidative stress (32). MT-positive cells can be observed infiltrating the lamina propria in patients with inflammatory and infectious colitis, with the number of MT-positive cells correlated with the severity of colitis (33).…”

TLR-Induced IL-12 and CCL2 Production by Myeloid Cells Is Dependent on Adenosine A3 Receptor–Mediated Signaling

“…Their expression is potently induced by metal exposure and oxidative stress but also by cytokine signaling and microbial challenge (22)(23)(24)(25). In myeloid cells, there is ample evidence for an important role of metallothioneins in the maintenance of intracellular zinc homoeostasis (26)(27)(28). Manipulation of intracellular and extracellular zinc levels can be used to modulate the phenotype of myeloid cells (29)(30)(31), and different studies have identified a role for zinc signaling in kinase and phosphatase functions (32,33).…”

Expression and regulation of metallothioneins in myometrium and fetal membranes

“…Bacterial and/or viral pathogens can induce an inflammatory response leading to preterm labor by binding distinct TLRs on gestational tissues . In nongestational tissues, MT expression is upregulated by various TLR ligands where they have been implicated in regulating inflammatory reactions and infection . To elucidate whether MTs are also increased in association with preterm pregnancies complicated by bacterial infection, amnion obtained from women with or without histologically confirmed chorioamnionitis was compared.…”