Innate Immunity

Metal-Mediated Innate Defense#

The innate immune system deploys metals as weapons. Calprotectin (S100A8/A9): Released by neutrophils; sequesters zinc and manganese, starving pathogens of essential cofactors. Lactoferrin: Binds free iron at mucosal surfaces; denies iron to siderophore-dependent pathogens. Hepcidin: IL-6-induced master iron regulator; sequesters systemic iron during infection.

Lipocalin-2: Neutralizes bacterial enterobactin (the strongest known siderophore). Copper burst: Macrophages pump toxic copper into phagosomes to kill engulfed bacteria. Zinc intoxication: Macrophages deliver lethal zinc doses to Salmonella-containing vacuoles.

Microbiome Shaping#

The innate immune system shapes the microbiome, and the microbiome shapes innate immunity. TLR signaling: Microbial LPS (TLR4), lipoteichoic acid (TLR2), flagellin (TLR5), and CpG DNA (TLR9) train innate immune responses.^{[1]Esophageal microbial dysbiosis impairs mucosal barrier integrity via toll-like receptor 2 pathway in patients with gastroesophageal reflux symptomsChen S, Jiang D, Zhuang Q et al. · 2024Open reference 1 ↓}

Peptidoglycan recognition proteins (PGRPs): Kill bacteria via metal-mediated oxidative, thiol, and osmotic stress—a direct intersection of innate immunity and metal toxicity.^{[2]Kashyap et al. 2014 — Peptidoglycan Recognition Proteins Kill Bacteria by Inducing Oxidative, Thiol, and Metal StressDipika R. Kashyap, Minhui Wang, Li-Hung Liu et al. · 2014Open reference 2 ↓}

Intestinal immunity: Iron homeostasis in the gut directly modulates innate immune cell function.^{[3]Mechanism of Iron Ion Homeostasis in Intestinal Immunity and Gut Microbiota RemodelingHonghong Bao, Yi Wang, Hanlin Xiong et al. · 2024Open reference 3 ↓} Crohn's disease: Defective innate immunity (NOD2 mutations) leads to impaired bacterial clearance and chronic Metal-Driven Inflammation.^{[4]Intestinal Microbiota and the Innate Immune System - a Crosstalk in Crohn's Disease PathogenesisHaag LM, Siegmund B · 2015Open reference 4 ↓}