Mycolactone toxin induces an inflammatory response by targeting the IL-1β pathway: Mechanistic insight into Buruli ulcer pathophysiology.
Mycolactone toxin induces an inflammatory response by targeting the IL-1β pathway: Mechanistic insight into Buruli ulcer pathophysiology.
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霉菌霉素毒素通过靶向IL-1β途径诱导炎症反应：对Buruli溃疡病理生理学的机械洞察力。
DOI：
10.1371/journal.ppat.1009107
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发表时间：
2020-12
期刊：
影响因子：
6.7
通讯作者：
Marion E
中科院分区：
文献类型：
--
作者：
Foulon M;Robbe-Saule M;Manry J;Esnault L;Boucaud Y;Alcaïs A;Malloci M;Fanton d'Andon M;Beauvais T;Labarriere N;Jeannin P;Abel L;Saint-André JP;Croué A;Delneste Y;Boneca IG;Marsollier L;Marion E
霉菌内酯是一种类脂毒素，是布鲁里溃疡的病原菌溃烂分枝杆菌的主要毒力因子。在疾病的早期阶段，通过其细胞毒性和免疫抑制活性，它参与了病变的发展，但对后期的情况知之甚少。在这里，我们回顾了霉菌内酯在疾病预后中的作用，并首次证明了这种毒素的促炎潜力。我们发现，溃烂分枝杆菌产生的含有分枝杆菌内酯的胞外小泡以TLR2依赖的方式诱导一种强有力的促炎细胞因子IL-1β的产生，靶向NLRP3/1炎症体。我们表明我们的数据在生理环境中是相关的。体内注射这些含有霉菌内酯的囊泡可引起强烈的局部炎症反应和组织损伤，而皮质类固醇可以预防这一反应。最后，在小鼠和布鲁里溃疡患者的感染组织中检测到了几种可溶性的促炎因子，包括IL-1β。我们的结果重新审视了布鲁里溃疡的病理生理学，提供了新的见解，从而为开发新的治疗策略铺平了道路，考虑到了霉菌内酯的促炎潜力。布鲁里溃疡是一种被忽视的热带疾病，主要发生在西非和中非的贫穷农村地区。这种皮肤病是由溃烂分枝杆菌引起的，溃烂分枝杆菌是与结核分枝杆菌和麻风分枝杆菌同属一科的细菌。皮肤损伤是由一种名为霉菌内酯的细胞毒素引起的，这种毒素也被认为是一种免疫抑制剂和抗炎分子。然而，布鲁里溃疡的病变以慢性皮肤炎症为特征，并招募细胞免疫细胞试图对抗溃疡分枝杆菌。我们的工作允许调和先前的观察结果。我们在巨噬细胞上的体外实验发现，溃烂分枝杆菌产生的含有分枝杆菌内酯的胞外小泡可诱导一种强有力的促炎分子IL-1β的产生，而其他促炎可溶性因子则受到抑制。我们还在溃烂分枝杆菌感染的小鼠模型以及布鲁里溃疡患者的活检组织中检测到IL-1β蛋白。要全面了解布鲁里溃疡的病理生理学，必须考虑到霉菌素的促炎作用。
Mycolactone, a lipid-like toxin, is the major virulence factor of Mycobacterium ulcerans, the etiological agent of Buruli ulcer. Its involvement in lesion development has been widely described in early stages of the disease, through its cytotoxic and immunosuppressive activities, but less is known about later stages. Here, we revisit the role of mycolactone in disease outcome and provide the first demonstration of the pro-inflammatory potential of this toxin. We found that the mycolactone-containing mycobacterial extracellular vesicles produced by M. ulcerans induced the production of IL-1β, a potent pro-inflammatory cytokine, in a TLR2-dependent manner, targeting NLRP3/1 inflammasomes. We show our data to be relevant in a physiological context. The in vivo injection of these mycolactone-containing vesicles induced a strong local inflammatory response and tissue damage, which were prevented by corticosteroids. Finally, several soluble pro-inflammatory factors, including IL-1β, were detected in infected tissues from mice and Buruli ulcer patients. Our results revisit Buruli ulcer pathophysiology by providing new insight, thus paving the way for the development of new therapeutic strategies taking the pro-inflammatory potential of mycolactone into account. Buruli ulcer is a neglected tropical disease occurring mainly in poor rural areas of West and Central Africa. This cutaneous disease is caused by Mycobacterium ulcerans, a bacterium belonging to the same family as M. tuberculosis and M. leprae. The skin lesions are caused by a cytotoxic toxin named mycolactone, also known to act as an immunosuppressor and an anti-inflammatory molecule. However, Buruli ulcer lesions are characterized by a chronic cutaneous inflammation with a recruitment of cellular immune cells trying to counteract M. ulcerans. Our work allows for a reconcilitation of previous observations. We found by in vitro experiment on macrophages that the mycolactone-containing mycobacterial extracellular vesicles produced by M. ulcerans induced the production of IL-1β, a potent pro-inflammatory molecule, while other pro-inflammatory soluble factors are inhibited. We also detected IL-1β protein in a mouse model of M. ulcerans infection as well as in biopsies of Buruli ulcer patients. The pro-inflammatory potential of mycolacone has to be taken into account to understand the full pathophysiology of Buruli ulcer.
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DOI：
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发表时间：
2016-12-12
期刊：
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影响因子：
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2014-06-06
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影响因子：
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10.1073/pnas.0902745106
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影响因子：
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