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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 3

Hepcidin is required for CXCL1 production and neutrophil recruitment.

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Hepcidin is required for CXCL1 production and neutrophil recruitment.
(A...
(A) Anti-CXCL1 or (C) anti–polymorphonuclear leucocyte (PMN) immunostainings on skin of Hamp1lox/lox and Hamp1Δker mice challenged with GAS. PerkinElmer’s Lamina multilabel slide scanner Panoramic Viewer software. (B) CXCL1 ELISA on lysates from GAS-infected skin biopsies of Hamp1lox/lox (n = 5) and Hamp1Δker mice (n = 6). (D) Neutrophil count from GAS-infected skin biopsies of Hamp1lox/lox (n = 5) and Hamp1Δker mice (n = 4). (E) Area of necrotic ulcers in skin of Hamp1lox/lox and Hamp1Δker mice during GAS infection; n = 7 per group. (F) Scheme of the study protocol. (G) Bacterial count in the skin of Hamp1lox/lox and Hamp1Δker mice injected daily with CXCL1 or PBS; n ≥ 4 per group. Statistical analysis was performed using a Student’s t test (B and D), a 2-way ANOVA followed by Tukey’s test (E), or a 1-way ANOVA followed by Tukey’s test (G). *P < 0.05; **P < 0.01.
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