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Epidermal hepcidin is required for neutrophil response to bacterial infection
Mariangela Malerba, … , Jacques R.R. Mathieu, Carole Peyssonnaux
Mariangela Malerba, … , Jacques R.R. Mathieu, Carole Peyssonnaux
Published October 10, 2019
Citation Information: J Clin Invest. 2020;130(1):329-334. https://doi.org/10.1172/JCI126645.
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Concise Communication Infectious disease

Epidermal hepcidin is required for neutrophil response to bacterial infection

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Abstract

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.

Authors

Mariangela Malerba, Sabine Louis, Sylvain Cuvellier, Srikanth Mairpady Shambat, Camille Hua, Camille Gomart, Agnès Fouet, Nicolas Ortonne, Jean-Winoc Decousser, Annelies S. Zinkernagel, Jacques R.R. Mathieu, Carole Peyssonnaux

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Figure 1

Keratinocyte hepcidin prevents bacterial systemic spread.

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Keratinocyte hepcidin prevents bacterial systemic spread.
IHC with or wi...
IHC with or without primary antibody detecting (A) hepcidin (in brown) on sections of cutaneous human biopsies of GAS NF patients and healthy control using PerkinElmer’s Lamina multilabel slide scanner Panoramic Viewer software. (B) Real-time reverse transcription PCR (qPCR) for hepcidin from GAS-infected human 3D organotypic skin equivalent model; n = 4 per group. (C) qPCR for hepcidin in murine GAS-infected skin; n ≥ 3 per group. (D) Hepcidin (in blue) and K14 (in brown) IHC on cutaneous biopsies of WT mice challenged or not with GAS. Scale bars: 100 μm. Leica DMI3000B microscope, Leica DFC310FX camera, 5/0.4; Leica LAS Core software. (E) Generation of Hamp1Δker mice. (F) Plasma iron, ferritin, transferrin, and skin iron levels in Hamp1lox/lox and Hamp1Δker mice; n ≥ 4 per group. (G) Bacterial count in skin, blood, and spleen of Hamp1lox/lox and Hamp1Δker mice 4 days after injection with GAS; n ≥ 10 per group. (H) Weight variation of Hamp1lox/lox and Hamp1Δker mice during infection; n = 10 per group. Statistical analysis was performed using a Mann Whitney test (B, C, F, and G) or a 2-way ANOVA followed by Tukey’s test for weight kinetics (H). *P < 0.05; **P < 0.01; ***P < 0.001.
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