Department of Microbial Sciences, School of Bioscience and Medicine, Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom.
Brighton and Sussex Medical School, University of Sussex, Brighton, United Kingdom.
Front Immunol. 2022 Jan 26;12:788146. doi: 10.3389/fimmu.2021.788146. eCollection 2021.
Buruli ulcer (BU), caused by , is a devastating necrotizing skin disease. Key to its pathogenesis is mycolactone, the exotoxin virulence factor that is both immunosuppressive and cytotoxic. The discovery that the essential Sec61 translocon is the major cellular target of mycolactone explains much of the disease pathology, including the immune blockade. Sec61 inhibition leads to a loss in production of nearly all cytokines from monocytes, macrophages, dendritic cells and T cells, as well as antigen presentation pathway proteins and costimulatory molecules. However, there has long been evidence that the immune system is not completely incapable of responding to infection. In particular, IL-1β was recently shown to be present in BU lesions, and to be induced from -exposed macrophages in a mycolactone-dependent manner. This has important implications for our understanding of BU, showing that mycolactone can act as the "second signal" for IL-1β production without inhibiting the pathways of unconventional secretion it uses for cellular release. In this Perspective article, we validate and discuss this recent advance, which is entirely in-line with our understanding of mycolactone's inhibition of the Sec61 translocon. However, we also show that the IL-1 receptor, which uses the conventional secretory pathway, is sensitive to mycolactone blockade at Sec61. Hence, a more complete understanding of the mechanisms regulating IL-1β function in skin tissue, including the transient intra-macrophage stage of infection, is urgently needed to uncover the double-edged sword of IL-1β in BU pathogenesis, treatment and wound healing.
布鲁里溃疡（BU）由 引起，是一种破坏性的坏死性皮肤疾病。其发病机制的关键是分枝杆菌内酯，这是一种外毒素毒力因子，具有免疫抑制和细胞毒性。发现必需的 Sec61 易位体是分枝杆菌内酯的主要细胞靶标，这解释了疾病病理的大部分内容，包括免疫阻断。Sec61 抑制导致单核细胞、巨噬细胞、树突状细胞和 T 细胞以及抗原呈递途径蛋白和共刺激分子几乎所有细胞因子的产生丧失。然而，长期以来有证据表明，免疫系统并非完全无法对 感染作出反应。特别是，最近发现 IL-1β存在于 BU 病变中，并以分枝杆菌内酯依赖性方式从暴露于 的巨噬细胞中诱导产生。这对我们理解 BU 具有重要意义，表明分枝杆菌内酯可以作为 IL-1β产生的“第二信号”，而不会抑制其用于细胞释放的非常规分泌途径。在这篇观点文章中，我们验证和讨论了这一最新进展，这完全符合我们对分枝杆菌内酯抑制 Sec61 易位体的理解。然而，我们还表明，IL-1 受体，它使用常规分泌途径，对 Sec61 处的分枝杆菌内酯阻断敏感。因此，迫切需要更全面地了解调节皮肤组织中 IL-1β功能的机制，包括 感染的短暂巨噬细胞内阶段，以揭示 IL-1β在 BU 发病机制、治疗和伤口愈合中的双刃剑作用。
