Hemozoin Promotes Lung Inflammation via Host Epithelial Activation.
Hemozoin Promotes Lung Inflammation via Host Epithelial Activation.
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DOI：
10.1128/mbio.02399-20
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发表时间：
2021-02-09
期刊：
影响因子：
6.4
通讯作者：
Prince AS
中科院分区：
文献类型：
--
作者：
Shah SS;Fidock DA;Prince AS
呼吸窘迫（RD）是严重疟疾的一种并发症，与感染恶性疟原虫的非洲儿童的死亡风险特别高有关。对RD的病理生理学基础仍知之甚少，并且对该疾病进行了预防性管理。重症疟疾的呼吸窘迫与高死亡率有关，但其发病机制仍不清楚。疟原虫色素疟原虫色素（HZ）在严重疟疾的靶器官（包括肺）中含量丰富，已知是吞噬细胞的有效先天免疫激活剂。我们假设HZ还可能刺激肺上皮活化，从而加剧肺部炎症。我们在这里表明，气道上皮细胞刺激HZ经历了全球转录重编程和细胞表面蛋白表达的变化，包括上皮细胞活化表型。促炎信号被诱导，关键的细胞粘附分子被上调，包括与严重疟疾相关的几种分子，如CD36和ICAM 1。上皮和细胞外基质重塑途径发生转变，包括诱导关键金属蛋白酶和调节上皮连接。HZ诱导的整个程序用于促进炎症和中性粒细胞迁移，并在HZ诱导的急性肺炎的小鼠模型中重现。总之，我们的数据表明疟原虫色素在刺激上皮细胞活化中的直接作用，这可能会加强疟疾的肺部炎症。
Respiratory distress (RD) is a complication of severe malaria associated with a particularly high risk for death in African children infected with the parasite Plasmodium falciparum. The pathophysiology underlying RD remains poorly understood, and the condition is managed supportively. Respiratory distress in severe malaria is associated with high mortality, but its pathogenesis remains unclear. The malaria pigment hemozoin (HZ) is abundant in target organs of severe malaria, including the lungs, and is known to be a potent innate immune activator of phagocytes. We hypothesized that HZ might also stimulate lung epithelial activation and thereby potentiate lung inflammation. We show here that airway epithelium stimulated with HZ undergoes global transcriptional reprogramming and changes in cell surface protein expression that comprise an epithelial activation phenotype. Proinflammatory signaling is induced, and key cytoadherence molecules are upregulated, including several associated with severe malaria, such as CD36 and ICAM1. Epithelial and extracellular matrix remodeling pathways are transformed, including induction of key metalloproteases and modulation of epithelial junctions. The overall program induced by HZ serves to promote inflammation and neutrophil transmigration, and is recapitulated in a murine model of HZ-induced acute pneumonitis. Together, our data demonstrate a direct role for hemozoin in stimulating epithelial activation that could potentiate lung inflammation in malaria.