The polypeptide antibiotic polymyxin B acts as a pro-inflammatory irritant by preferentially targeting macrophages
The polypeptide antibiotic polymyxin B acts as a pro-inflammatory irritant by preferentially targeting macrophages
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DOI：
10.1038/s41429-021-00490-7
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发表时间：
2021-11-25
影响因子：
3.3
通讯作者：
Matsuzawa, Atsushi
中科院分区：
文献类型：
--
作者：
Kagi, Tomohiro;Naganuma, Rio;Matsuzawa, Atsushi
多粘菌素B（PMB）是一种重要的抗生素，对多重耐药细菌，如多重耐药铜绿假单胞菌（MDRP）。然而，PMB的临床应用是有限的，因为PMB引起严重的副作用，如肾毒性和神经毒性，可能是由于其细胞毒性活性。然而，PMB的细胞毒性机制知之甚少。在这项研究中，我们发现巨噬细胞对PMB特别敏感，与其他类型的细胞相比，包括成纤维细胞和近端小管（PT）细胞。值得注意的是，PMB诱导的巨噬细胞坏死允许被动释放高迁移率族蛋白1（HMGB 1）。此外，在将PMB暴露于巨噬细胞后，刺激了由促进促炎细胞因子如白细胞介素-1 β（IL-1 β）释放的含NLR家族pyrin结构域3（NLRP 3）炎性体介导的先天免疫系统。有趣的是，PMB诱导的IL-1 β释放发生在没有孔形成蛋白gasdermin D（GSDMD）的情况下，这支持了PMB导致质膜破裂伴坏死的观点。新出现的证据表明，从巨噬细胞释放的HMGB 1和IL-1 β都有助于过度炎症，从而促进各种疾病的发病机制，包括肾毒性和神经毒性。因此，PMB在巨噬细胞中的这些生化特性可能与不良器官毒性的诱导有关，这为PMB相关副作用的机制提供了新的见解。
Polymyxin B (PMB) is an essential antibiotic active against multidrug-resistant bacteria, such as multidrug-resistant Pseudomonas aeruginosa (MDRP). However, the clinical use of PMB is limited, because PMB causes serious side effects, such as nephrotoxicity and neurotoxicity, probably due to its cytotoxic activity. However, cytotoxic mechanisms of PMB are poorly understood. In this study, we found that macrophages are particularly sensitive to PMB, when compared with other types of cells, including fibroblasts and proximal tubule (PT) cells. Of note, PMB-induced necrosis of macrophages allowed passive release of high mobility group box 1 (HMGB1). Moreover, upon exposure of PMB to macrophages, the innate immune system mediated by the NLR family pyrin domain containing 3 (NLRP3) inflammasome that promotes the release of pro-inflammatory cytokines such as interleukin-1 beta (IL-1 beta) was stimulated. Interestingly, PMB-induced IL-1 beta release occurred in the absence of the pore-forming protein gasdermin D (GSDMD), which supports the idea that PMB causes plasma membrane rupture accompanying necrosis. Emerging evidence has suggested that both HMGB1 and IL-1 beta released from macrophages contribute to excessive inflammation that promote pathogenesis of various diseases, including nephrotoxicity and neurotoxicity. Therefore, these biochemical properties of PMB in macrophages may be associated with the induction of the adverse organ toxicity, which provides novel insights into the mechanisms of PMB-related side effects.