PubMed: https://pubmed.ncbi.nlm.nih.gov/34483037/
What the review examined
This 2021 review by Andrew J. Monteith and Eric P. Skaar in Trends in Endocrinology and Metabolism synthesizes how the availability of nutrient transition metals governs immune-cell function during bacterial infection. Its central argument is that nutritional immunity—the host's deliberate withholding or overloading of metals to control pathogens—has a second, underappreciated role: the same metal fluxes that target microbes also regulate the immune cells that produce them.
The authors focus on four essential transition metals: zinc (Zn), iron (Fe), manganese (Mn), and copper (Cu). Each serves as a structural or catalytic cofactor for hundreds of proteins, so its concentration is tightly controlled to preserve essential biochemistry while avoiding toxicity. Inflammation disrupts this steady state, producing a heterogeneous battlefield of metal-replete and metal-deplete niches in which immune cells must operate.
The key findings: metals as immune-cell regulators
Zinc availability affects immune cells in a cell-type-specific and often opposing manner. Zinc restriction impairs neutrophil phagocytosis yet can enhance macrophage phagocytosis, and zinc is required for NLRP3 inflammasome activation and for amplifying LPS-driven inflammatory signaling. Zinc is therefore not simply 'good' or 'bad' for immunity—its effect depends on the cell and the compartment.
Iron handling shapes macrophage antimicrobial capacity. Intracellular iron accumulation suppresses inducible nitric oxide synthase (iNOS) expression, blunting a macrophage's ability to clear intracellular pathogens, while heme sensing through heme oxygenase-1 helps immune cells distinguish live from dead bacteria. Manganese and copper are less studied but consequential: manganese supports neutrophil attachment and respiratory burst, copper deficiency reduces oxidative killing capacity, and copper excess drives unsustainable activation and increased apoptosis.
The mechanism: sequestration proteins and phagosomal metal weapons
The best-characterized effector of nutritional immunity is calprotectin (the S100A8/S100A9 heterodimer), which makes up nearly half of the cytosolic protein content of neutrophils. Calprotectin chelates zinc, manganese, iron, and nickel at sites of inflammation, starving pathogens such as Staphylococcus aureus and Mycobacterium tuberculosis. Complementary iron-withholding is achieved by hepcidin (blocking iron export), lactoferrin, and lipocalin-2, while metallothioneins buffer intracellular zinc and help set macrophage polarization—MT1/MT2 favor pro-inflammatory M1 states and MT3 supports anti-inflammatory M2 states.
Inside the phagosome, immune cells wield metals as weapons. A 'brass dagger' strategy pumps toxic surges of zinc and copper into the phagosomal compartment to poison engulfed microbes, while the transporter NRAMP1 (SLC11A1) simultaneously depletes iron, manganese, and magnesium to starve them. Crucially, many of these metal-binding proteins are pleiotropic: calprotectin and related S100 proteins also act as damage-associated molecular patterns (DAMPs), chemoattractants, and signaling molecules, so metal handling and immune signaling are deeply intertwined.
How it fits the metal–microbiome–disease axis
This review concerns immune cells and pathogens rather than the commensal microbiome directly, so the connection to the broader metal–microbiome–disease axis is mechanistic and extrapolative rather than demonstrated within the paper itself. Its relevance is foundational: it establishes that host control of metal availability is a primary lever over both microbial growth and immune-cell behavior. The same metal-withholding and metal-intoxication systems that constrain pathogens (calprotectin, lipocalin-2, hepcidin, phagosomal metal pumps) also shape which microbes can colonize a niche—a principle that extends from acute infection to the resident gut and airway microbiome.
Because these systems operate on such narrow metal margins, exogenous perturbation of body metal pools is biologically plausible as a disruptor. Heavy-metal exposure (for example cadmium, lead, or arsenic) and dietary imbalances in essential metals can alter the size and localization of the very zinc, iron, manganese, and copper pools this review shows are decisive for immune function—potentially skewing nutritional immunity, reshaping the microbiome, and contributing to disease. That mechanistic bridge is a hypothesis motivated by this foundational biology, not a finding of this specific review, and should be read as such.
Key findings
- Nutritional immunity does double duty: manipulating zinc, iron, manganese, and copper availability both controls pathogens and tunes the host's own neutrophils and macrophages.
- Zinc has opposing, cell-type-specific effects—restriction impairs neutrophil phagocytosis but can enhance macrophage phagocytosis, and zinc is required for NLRP3 inflammasome activation.
- Intracellular iron accumulation suppresses inducible nitric oxide synthase (iNOS), weakening macrophage killing of intracellular pathogens.
- Calprotectin (S100A8/A9) is ~50% of neutrophil cytosolic protein and sequesters zinc, manganese, iron, and nickel at infection sites.
- Phagosomes deploy metals offensively: a 'brass dagger' floods zinc and copper to intoxicate microbes while NRAMP1 depletes iron and manganese to starve them.
- Metal-sequestering proteins are pleiotropic, also acting as DAMPs, chemoattractants, and signaling molecules that link metal status to immune signaling.
Frequently asked questions
What is nutritional immunity?
Nutritional immunity is the host defense strategy of controlling the availability of essential transition metals—zinc, iron, manganese, and copper—to starve invading pathogens of the metals they need or, conversely, to flood them with toxic amounts. This review highlights that the same process also regulates the function of the host's own immune cells.
How does zinc affect immune cells during infection?
Zinc's effects are cell-type specific and sometimes opposite. Zinc restriction impairs neutrophil phagocytosis but can enhance macrophage phagocytosis. Zinc is also required for NLRP3 inflammasome activation and amplifies LPS-driven inflammatory signaling, so its impact depends on the cell type and cellular compartment involved.
What is calprotectin and why does it matter?
Calprotectin is the S100A8/S100A9 heterodimer, making up roughly half of the cytosolic protein in neutrophils. It chelates zinc, manganese, iron, and nickel at sites of inflammation to starve pathogens such as Staphylococcus aureus and Mycobacterium tuberculosis, and it doubles as a signaling molecule and damage-associated molecular pattern (DAMP).
How do immune cells use metals as weapons inside phagosomes?
After engulfing a microbe, immune cells manipulate phagosomal metal levels. A 'brass dagger' mechanism pumps toxic surges of zinc and copper into the phagosome to poison the pathogen, while the transporter NRAMP1 simultaneously removes iron, manganese, and magnesium to starve it—exploiting both the essentiality and the toxicity of these metals.