Hepcidin induction by pathogens and pathogen-derived molecules is strongly dependent on interleukin-6 Original paper

What was studied?

This original experimental study investigated IL-6-dependent hepcidin induction during infection and after exposure to pathogen-associated molecular patterns (PAMPs), aiming to clarify whether bacterial versus viral infections differentially increase hepatic hepcidin and which innate immune pathways are truly required. Hepcidin is the liver-derived hormone that lowers circulating iron by degrading ferroportin, producing inflammation-associated hypoferremia—often interpreted as “nutritional immunity” that starves microbes of iron. The authors systematically compared a common bacterial pneumonia model (Streptococcus pneumoniae serotype 3) and a viral pneumonia model (influenza A/PR8), then tested a broad panel of microbial ligands activating Toll-like receptors (TLRs) and NOD-like receptors (NLRs) in vivo and in primary human hepatocytes. The central mechanistic question was whether hepcidin induction is directly driven by pattern-recognition receptor signaling or is predominantly mediated through interleukin-6 (IL-6).

Who was studied

The in vivo work used 6-week-old male C57BL/6 wild-type mice and IL-6 knockout mice on the same background, preconditioned with a low-iron diet to suppress baseline hepcidin and reveal dynamic induction during infection (pages 3–4). Mice received oropharyngeal inoculation with S. pneumoniae (10⁴ or 5×10⁴ CFU) or influenza PR8 (100 or 500 PFU) and were assessed at 2 and 5 days for hepatic hepcidin mRNA responses (pages 3–5). For translational relevance, the investigators also studied fresh primary human hepatocytes (from donor livers) and human Kupffer cells; hepatocytes were stimulated directly with PAMPs or indirectly using Kupffer cell–conditioned media, with or without neutralizing antibodies to IL-6 and the IL-6 receptor.

Most important findings

Both bacterial and viral respiratory infections robustly induced hepatic hepcidin in wild-type mice, reaching ~10³–10⁴+ fold increases during S. pneumoniae infection and ~10³ fold increases by day 5 after influenza PR8. Strikingly, IL-6 knockout mice failed to significantly induce hepcidin in either infection model, indicating near-complete IL-6 dependence in vivo. When testing microbial ligands, extracellularly sensed PAMPs (TLR1/2, TLR2/6, TLR4, TLR5) and some endosomal ligands (notably TLR3 and TLR9) increased hepatic hepcidin in wild-type mice, whereas TLR7 and cytosolic NOD1/NOD2 ligands did not reliably do so under these conditions. In IL-6 knockout mice, PAMP-driven hepcidin induction was abolished or markedly blunted, with only residual responses to LPS and CpG ODN. In primary human hepatocytes, the pattern largely mirrored the mouse data: strong induction by extracellular TLR agonists and poly(I:C), minimal induction by TLR7/9 and NOD ligands. Neutralizing IL-6/IL-6R antibodies reduced hepatocyte hepcidin responses to inducing PAMPs by a geometric mean ~17-fold, reinforcing IL-6 as the dominant mediator. Although not a “microbiome” paper, the work is highly relevant for microbial-signature databases because it links specific pathogen signals (Gram-positive pneumonia, influenza, and defined PAMP classes) to a conserved host iron-withholding program.

Key implications

Clinically, these data reinforce that infection-associated hypoferremia and anemia-of-inflammation are not merely “direct” microbial effects but are largely orchestrated by IL-6 signaling upstream of hepcidin across both bacterial and viral respiratory infections. This helps explain why IL-6/IL-6R–targeted therapies could lower hepcidin and improve iron availability in inflammatory states, while also raising biologically plausible concerns about altering iron restriction during active infection. For microbiome and infectious-disease translational work, the study provides a mechanistic framework: specific microbial molecular patterns—especially those sensed extracellularly via TLRs—trigger a conserved IL-6 → hepcidin axis that can be cataloged as a host-response signature linked to particular pathogen exposures.

Citation

Rodriguez R, Jung CL, Gabayan V, et al. Hepcidin induction by pathogens and pathogen-derived molecules is strongly dependent on interleukin-6. Infect Immun. 2014;82(2):745-752. doi:10.1128/IAI.00983-13