A Macrophage Response to Mycobacterium leprae Phenolic Glycolipid Initiates Nerve Damage in Leprosy.,Cell

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A Macrophage Response to Mycobacterium leprae Phenolic Glycolipid Initiates Nerve Damage in Leprosy.
Cell ( IF 45.5 ) Pub Date : 2017-Aug-24 , DOI: 10.1016/j.cell.2017.07.030
Cressida A Madigan ₁ , C J Cambier ₂ , Kindra M Kelly-Scumpia ₃ , Philip O Scumpia ₃ , Tan-Yun Cheng ₄ , Joseph Zailaa ₅ , Barry R Bloom ₆ , D Branch Moody ₄ , Stephen T Smale ₇ , Alvaro Sagasti ₈ , Robert L Modlin ₉ , Lalita Ramakrishnan ₁₀

Affiliation

Division of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Microbiology, University of Washington, Seattle, WA 98195, USA.
Department of Immunology, University of Washington, Seattle, WA 98195, USA.
Division of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Harvard School of Public Health, Boston, MA 02115, USA.
Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Division of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Department of Microbiology, University of Washington, Seattle, WA 98195, USA; Department of Immunology, University of Washington, Seattle, WA 98195, USA; Department of Medicine, University of Washington, Seattle, WA 98195, USA; MRC Laboratory of Molecular Biology, Molecular Immunity Unit, Department of Medicine, University of Cambridge, Cambridge CB2 OQH, UK.

Mycobacterium leprae causes leprosy and is unique among mycobacterial diseases in producing peripheral neuropathy. This debilitating morbidity is attributed to axon demyelination resulting from direct interaction of the M. leprae-specific phenolic glycolipid 1 (PGL-1) with myelinating glia and their subsequent infection. Here, we use transparent zebrafish larvae to visualize the earliest events of M. leprae-induced nerve damage. We find that demyelination and axonal damage are not directly initiated by M. leprae but by infected macrophages that patrol axons; demyelination occurs in areas of intimate contact. PGL-1 confers this neurotoxic response on macrophages: macrophages infected with M. marinum-expressing PGL-1 also damage axons. PGL-1 induces nitric oxide synthase in infected macrophages, and the resultant increase in reactive nitrogen species damages axons by injuring their mitochondria and inducing demyelination. Our findings implicate the response of innate macrophages to M. leprae PGL-1 in initiating nerve damage in leprosy.

中文翻译：

巨噬细胞对麻风分枝杆菌酚糖脂的反应引发麻风病的神经损伤。

麻风分枝杆菌引起麻风病，并且在引起周围神经病变的分枝杆菌疾病中是独一无二的。这种令人衰弱的发病率归因于麻风分枝杆菌特异性酚糖脂 1 (PGL-1) 与髓鞘神经胶质细胞直接相互作用及其随后的感染导致的轴突脱髓鞘。在这里，我们使用透明的斑马鱼幼虫来可视化麻风分枝杆菌引起的神经损伤的最早事件。我们发现脱髓鞘和轴突损伤不是由麻风分枝杆菌直接引发的，而是由巡逻轴突的受感染巨噬细胞引发的。脱髓鞘发生在亲密接触的部位。 PGL-1 赋予巨噬细胞这种神经毒性反应：感染表达 PGL-1 的 M. marinum 的巨噬细胞也会损害轴突。 PGL-1 在受感染的巨噬细胞中诱导一氧化氮合酶，由此产生的活性氮物质增加，通过损伤线粒体并诱导脱髓鞘来损害轴突。我们的研究结果表明先天巨噬细胞对麻风分枝杆菌 PGL-1 的反应引发了麻风病的神经损伤。

更新日期：2017-08-24

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