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.

中文翻译：

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表皮铁调素是中性粒细胞对细菌感染的反应所必需的

对于复杂的感染和免疫力低下的患者，迫切需要新的辅助治疗方法。坏死性筋膜炎（NF）是一种破坏性皮肤和软组织感染。尽管使用了全身性抗生素治疗并彻底清除了坏死组织，但致死率仍然很高。关键的铁调节激素铁调素最初被鉴定为阳离子抗微生物肽（AMP），但从未研究过它在皮肤中（AMP产生的主要部位）的假定表达和作用。我们在这里报告说，A组链球菌患者的皮肤中诱导了铁调素的产生（GAS）NF。在GAS诱导的NF模型中，从最初的组织焦点出发，在角质形成细胞中缺乏铁调素的小鼠无法限制感染的系统性传播。出乎意料的是，这种作用归因于其促进角质形成细胞产生CXCL1趋化因子的能力，从而导致嗜中性白细胞募集。与CXCL1不同，铁调素对主要GAS蛋白酶的降解具有抗性，因此可以用作在感染组织中维持CXCL1稳态水平的库。最后，在感染部位注射合成铁调素可以限制或完全防止GAS感染的全身扩散，这表明铁调素激动剂可能对NF有治疗作用。