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

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 2

Hepcidin promotes CXCL1 production by keratinocytes.

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Hepcidin promotes CXCL1 production by keratinocytes. (A) GAS killing kin...
(A) GAS killing kinetics with 32 μM of LL-37 and hepcidin; n = 3 per group. Representative of 2 independent experiments. (B) GAS growth curve in the presence of penicillin G, LL-37, hepcidin, or PBS; n = 3 per group. Representative of 2 independent experiments. (C) Bacterial recovering at 1 hour and 3 hours following incubation of log-phase GAS with murine primary keratinocytes (KC) from Hamp1lox/lox and Hamp1Δker mice. Data are representative of 2 independent experiments performed in triplicate. (D) Cytokines measured with the V-PLEX Proinflammatory Panel1 kit in the culture supernatant of murine primary keratinocytes stimulated for 1 or 3 hours with hepcidin or PBS; n = 3 per group. Representative of 3 independent experiments. (E) IL-8 ELISA on the culture supernatant of HaCat or a human 3D skin equivalent model stimulated with 3.6 μM hepcidin; n ≥ 3 per group. (F) CXCL1 levels measured by ELISA in the culture supernatant of murine primary keratinocytes stimulated for 3 hours with 3.6 μM hepcidin in the presence of PBS or 100 μM FPN inhibitor (2D-014); n ≥ 3 per group. Representative of 3 independent experiments. (G) CXCL1 levels measured by ELISA on the culture supernatant of murine primary keratinocytes stimulated for 3 hours with 500 μM ferric ammonium citrate (FAC); n = 3 per group. Representative of 3 independent experiments. Statistical analysis was performed using a 2-way ANOVA followed by Tukey’s test (A, B, and D), unpaired Student’s t test (E and G), or a 1-way ANOVA followed by Tukey’s test (C and F). *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.