Zinc is an essential macronutrient, which play a crucial role in multiple cellular functions, including immune cell signaling. In zinc dyshomeostasis, which includes zinc deficiency, there are impairments in several cellular and organ function including overall immune function and increased susceptibility to infection. This shows that zinc cannot be overlooked in immune system and other cellular processes.
Zinc coordinates its signaling through two families of zinc transporters and metallothiones. The two families of zinc transporters are:
The Solute-linked carrier 39 (SLC39A or ZIP) family of zinc transporters, which transport zinc into the cytosol and out of the intracellular organelles and,
The Solute-liked carrier 30 (SLC30A or ZnT) family of zinc transporters, which transport zinc out of the cytosol and into the intracellular organelles.
Both ZIP and ZnT transporters are expressed in a cell- or tissue-specific manner.
Metallothione is a zinc-binding protein that functions as a reservoir of intracellular zinc. It has the ability to bind up to seven zinc ions per MT molecule. It also plays a crucial role in the distribution, transport and maintenance of intracellular zinc ions.
The Function of Zinc in Pathogen Invasion
Zinc regulates complex signaling pathways in immune cells. As a result, when an invasion by a pathogen occurs, the pathogen creates a conflict in which Zn becomes a shared resource.
In this battle-like state, the pathogen strives to utilize Zn for its biological functions at the expense o the host, while the host cells seek to reserve Zn and render it inaccessible for pathogen uptake. This strategy of the host cell curtails the growth of some pathogens, but there are some pathogen which resist this cellular mechanism by possessing strong Zn acquisition machineries that effectively compete with the host for Zn.
Excess zinc however, can exert toxic effects on microbial survival. And the immune cells have taken advantage of this to localize and fuel excessive Zn concentrations that intoxicate the pathogen without impacting host cells.
Zinc Signals in Monocytes and Macrophages.
The immune system provides two layers of defense against pathogens; they are innate and adaptive immunity. Innate immunity, which is the frontier of host defense, involves the recognition of pathogen-associated molecular patterns (PAMPs), conserved structures of invading pathogens, and the immediate initiation of immune responses.
During invasion, mononuclear phagocytes of innate immunity immediately recognize invading pathogens through the sensing of PAMPs by pathogen-recognition receptors (PRR), including Toll-like receptors (TLRs). Upon PAMP engagement, individual TLRs differentially recruit adaptor molecules such as MyD88, TRIF, TIRAP-dependent NF-kB, MARK, PI3K, and the TRIF/TRAM-dependent IRF3 pathway, and elicits a variety of monocyte and macrophage effectors’ functions.
Signaling through TRIF activates several transcription factors, including NF-kB, IRF3, and AP-1. This leads to the production of cytokines and type-1 IFN, as well as maturation of myeloid dendric cells. Biological responses from TRIF-dependent signaling depends on both the type of cell responding and the particular TLR that is activated.
In TLR4 signaling, the TLR4 TIR domain use TRAM to recruit TRIF to the signaling complex, either by operating from the plasma membrane or from the endosomes. Localization of TRAM to the endosomes is necessary for IRF3 activation in the TRIF-dependent pathway.
When a lipopolysaccharide binds to TLR4, it leads to rapid zinc influx into the cytoplasm of monocytes and macrophages, which triggers zinc-mediated regulation of major signaling pathways, including TRIF/TRAM pathway.
MyD88/TIRAP-dependent NF-kB pathway.
The NF-kB transcription factor is a central regulator of proinflammatory gene induction and functions in a variety of immune responses. It influences the expression of proinflammatory cytokines, Chemokines, acute phase proteins, matrix metalloproteinase, adhesion molecules, growth factors, and other factors involved in inflammatory responses.
Zinc regulates the NF-kB activity by suppressing LPS-induced activation of IKKB. This is through a mechanism that is initiated by the inhibition of cyclic nucleotide phosphodiesterase (PDE), and subsequent elevation of cGMP, cross-activation of protein kinase A (PKA), and inhibitory phosphorylation of protein kinase Raf-1.
Another mechanism which involves direct inhibition of IKK upstream of NF-kB is mediated by ZIP8, which increase intracellular zinc, and involves a direct binding of Zn to IKKB.