Dendritic cell-derived hepcidin sequesters iron from the microbiota to promote mucosal healing.
Bessman Nicholas J,Mathieu Jacques R R,Renassia Cyril,Zhou Lei,Fung Thomas C,Fernandez Keith C,Austin Christine,Moeller Jesper B,Zumerle Sara,Louis Sabine,Vaulont Sophie,Ajami Nadim J,Sokol Harry,Putzel Gregory G,Arvedson Tara,Sockolow Robbyn E,Lakhal-Littleton Samira,Cloonan Suzanne M,Arora Manish,Peyssonnaux Carole,Sonnenberg Gregory F
Science (New York, N.Y.)
Bleeding and altered iron distribution occur in multiple gastrointestinal diseases, but the importance and regulation of these changes remain unclear. We found that hepcidin, the master regulator of systemic iron homeostasis, is required for tissue repair in the mouse intestine after experimental damage. This effect was independent of hepatocyte-derived hepcidin or systemic iron levels. Rather, we identified conventional dendritic cells (cDCs) as a source of hepcidin that is induced by microbial stimulation in mice, prominent in the inflamed intestine of humans, and essential for tissue repair. cDC-derived hepcidin acted on ferroportin-expressing phagocytes to promote local iron sequestration, which regulated the microbiota and consequently facilitated intestinal repair. Collectively, these results identify a pathway whereby cDC-derived hepcidin promotes mucosal healing in the intestine through means of nutritional immunity.
Endogenous hepcidin and its agonist mediate resistance to selected infections by clearing non-transferrin-bound iron.
Stefanova Deborah,Raychev Antoan,Arezes Joao,Ruchala Piotr,Gabayan Victoria,Skurnik Mikael,Dillon Barbara J,Horwitz Marcus A,Ganz Tomas,Bulut Yonca,Nemeth Elizabeta
The iron-regulatory hormone hepcidin is induced early in infection, causing iron sequestration in macrophages and decreased plasma iron; this is proposed to limit the replication of extracellular microbes, but could also promote infection with macrophage-tropic pathogens. The mechanisms by which hepcidin and hypoferremia modulate host defense, and the spectrum of microbes affected, are poorly understood. Using mouse models, we show that hepcidin was selectively protective against siderophilic extracellular pathogens ( O9) by controlling non-transferrin-bound iron (NTBI) rather than iron-transferrin concentration. NTBI promoted the rapid growth of siderophilic but not nonsiderophilic bacteria in mice with either genetic or iatrogenic iron overload and in human plasma. Hepcidin or iron loading did not affect other key components of innate immunity, did not indiscriminately promote intracellular infections (), and had no effect on extracellular nonsiderophilic O8 or Hepcidin analogs may be useful for treatment of siderophilic infections.
Epidermal hepcidin is required for neutrophil response to bacterial infection.
Malerba Mariangela,Louis Sabine,Cuvellier Sylvain,Shambat Srikanth Mairpady,Hua Camille,Gomart Camille,Fouet Agnès,Ortonne Nicolas,Decousser Jean-Winoc,Zinkernagel Annelies S,Mathieu Jacques Rr,Peyssonnaux Carole
The Journal of clinical investigation
Novel approaches for adjunctive therapy are urgently needed for complicated infections and patients with compromised immunity. Necrotizing fasciitis (NF) is a destructive skin and soft tissue infection. Despite treatment with systemic antibiotics and radical debridement of necrotic tissue, lethality remains high. The key iron regulatory hormone hepcidin was originally identified as a cationic antimicrobial peptide (AMP), but its putative expression and role in the skin, a major site of AMP production, have never been investigated. We report here that hepcidin production is induced in the skin of patients with group A Streptococcus (GAS) NF. In a GAS-induced NF model, mice lacking hepcidin in keratinocytes failed to restrict systemic spread of infection from an initial tissue focus. Unexpectedly, this effect was due to its ability to promote production of the CXCL1 chemokine by keratinocytes, resulting in neutrophil recruitment. Unlike CXCL1, hepcidin is resistant to degradation by major GAS proteases and could therefore serve as a reservoir to maintain steady-state levels of CXCL1 in infected tissue. Finally, injection of synthetic hepcidin at the site of infection can limit or completely prevent systemic spread of GAS infection, suggesting that hepcidin agonists could have a therapeutic role in NF.
Low Serum Hepcidin Is Associated With Reduced Short-Term Survival in Adults With Acute Liver Failure.
Spivak Igor,Arora Jyoti,Meinzer Caitlyn,Durkalski-Mauldin Valerie,Lee William M,Trautwein Christian,Fontana Robert J,Strnad Pavel,
Hepatology (Baltimore, Md.)
The liver has an important role in iron homeostasis through the synthesis of the serum transporter transferrin and the iron hormone hepcidin. The aim of this study was to analyze parameters of iron metabolism in a multicenter cohort of adult patients with acute liver failure (ALF) and in an acetaminophen (APAP)-induced ALF mouse model. A representative subset of 121 adults with ALF (including 66 APAP-related patients) had baseline serum samples tested for ferritin, transferrin, iron, and hepcidin. Outcomes at 3 weeks after enrollment were categorized as spontaneous survivor (SS) versus death/transplantation (NSS). Mice were assessed before (controls) and 4 and 18 hours after injection of 300 mg/kg APAP. Patients with ALF as well as APAP-treated mice displayed increased ferritin and diminished serum hepcidin and hepcidin/ferritin ratio. SS had lower iron (29.1% vs. 34.5 µmol/L; P < 0.05) and transferrin saturation (60.9% vs. 79.1%; P < 0.01), but higher hepcidin levels (8.2 vs. 2.7 ng/mL; P < 0.001) and hepcidin/ferritin ratio (0.0047 vs. 0.0009; P < 0.001) than NSS. In a multivariate analysis, a log-transformed hepcidin-containing model displayed similar prognostic power as the established Acute Liver Failure Study Group index (C-statistic 0.87 vs. 0.85) and was better than Model for End-Stage Liver Disease score (C-statistic 0.76). In mice, hepcidin levels inversely correlated with the surrogate of liver injury. Conclusion: Our findings demonstrate that several serum iron parameters significantly associate with 3-week outcomes in adults with ALF. Among them, hepcidin decreases early during experimental APAP-induced ALF, is an independent predictor and might be a useful component of future prognostic scores.