Department of Experimental Medicine and Biochemical Science, University of Perugia, Polo Unico Sant'Andrea delle Fratte, 06132 Perugia, Italy.
J Antimicrob Chemother. 2014 Apr;69(4):1065-74. doi: 10.1093/jac/dkt457. Epub 2013 Nov 20.
Micafungin inhibits 1,3-β-D-glucan synthase and interferes with fungal cell wall synthesis. Clinically, micafungin has been shown to be efficacious for the treatment of invasive fungal infections. However, little is known about the immunomodulatory activity of micafungin in these infections.
We evaluated the immunomodulatory activity of escalating doses of micafungin in murine and human polymorphonuclear neutrophils (PMNs) in vitro and in vivo in different preclinical models of invasive aspergillosis, including mice deficient for selected innate immune receptors.
Micafungin was able to regulate PMN cytokine response to Aspergillus fumigatus conidia by decreasing the expression of tumour necrosis factor-α and increasing that of interleukin-10 (IL-10). In vivo, the therapeutic efficacy of micafungin was strictly dose-dependent, with the maximum activity observed at the highest dose, concomitant with reduced inflammatory pathology. The anti-inflammatory activity of micafungin required IL-10 and occurred through signalling via the TLR2/dectin-1 and TLR3/TRIF pathways.
Together, these findings suggest that the therapeutic efficacy of micafungin in aspergillosis is orchestrated by the activation of innate immune receptors affecting the inflammatory/anti-inflammatory balance during infection.
米卡芬净抑制 1,3-β-D-葡聚糖合酶并干扰真菌细胞壁合成。临床上，米卡芬净已被证明对治疗侵袭性真菌感染有效。然而，对于米卡芬净在这些感染中的免疫调节活性知之甚少。
我们评估了米卡芬净在体外和不同侵袭性曲霉菌病的临床前模型中对小鼠和人多形核粒细胞 (PMN) 的免疫调节活性，包括对选定先天免疫受体缺失的小鼠。
米卡芬净能够通过降低肿瘤坏死因子-α的表达和增加白细胞介素-10 (IL-10) 的表达来调节 PMN 对烟曲霉分生孢子的细胞因子反应。在体内，米卡芬净的治疗效果严格依赖于剂量，在最高剂量时观察到最大活性，同时炎症病理学减轻。米卡芬净的抗炎活性需要白细胞介素-10，并且通过 TLR2/dectin-1 和 TLR3/TRIF 途径的信号转导发生。
总之，这些发现表明，米卡芬净在曲霉菌病中的治疗效果是通过激活先天免疫受体来协调的，这些受体影响感染期间的炎症/抗炎平衡。
