The Role of Annexin A1 in Candida albicans and Candida auris infections in murine neutrophils

Annexin A1 (AnxA1) is an anti-inflammatory protein present in different cells in biological systems, especially expressed in macrophages and neutrophils. Since neutrophils play an important role in infections and inflammatory processes and the AnxA1 and its relation in Candida spp. infections is not well understood, our study highlights a perspective in AnxA1 as a target protein in control the immune response during fungi infection. C57BL/6 wild-type (WT) and AnxA1 knockout (AnxA1-/-) peritoneal neutrophils were coinfected with Candida albicans or Candida auris for 4 hours. High levels of COX-2 were observed in WT and AnxA1-/- neutrophils infected with C. albicans and C. auris coinfection. In addition, AnxA1-/- neutrophils exhibited a marked increase of phosphorylated ERK, p-38 and JNK levels after coinfection with both Candida spp. Lipidomics approach shows that lack of AnxA1 produced a marked difference in lipid profile of control or coinfected neutrophil supernatants compared to WT, especially glycerophospholipids and glycerolipids. In summary, our results showed that endogenous AnxA1 regulates neutrophil response under fungal infection and its lipid membrane organization and metabolism.

膜联蛋白A1（Annexin A1，简称AnxA1）是一类广泛分布于生物体内多种细胞的抗炎蛋白，尤其在巨噬细胞与中性粒细胞中高表达。鉴于中性粒细胞在感染及炎症进程中发挥关键作用，而AnxA1与念珠菌属（Candida spp.）感染的关联机制尚未得到充分阐明，本研究聚焦于将AnxA1作为调控真菌感染期间免疫应答的潜在靶标蛋白。本研究将C57BL/6野生型（WT）与AnxA1敲除（AnxA1 knockout）小鼠的腹腔中性粒细胞，分别与白色念珠菌（Candida albicans）或耳念珠菌（Candida auris）共感染4小时。实验结果显示，经白色念珠菌与耳念珠菌共感染的野生型及AnxA1敲除中性粒细胞中，环氧合酶2（COX-2）均呈现高表达水平。此外，经两种念珠菌共感染后，AnxA1敲除中性粒细胞内的磷酸化ERK（phosphorylated ERK）、p38（p-38）及c-Jun氨基末端激酶（JNK）水平显著升高。脂质组学（lipidomics）分析表明，与野生型小鼠相比，AnxA1缺失使对照组与共感染组的中性粒细胞上清液脂质谱产生显著差异，其中甘油磷脂与甘油脂类的变化尤为突出。综上，本研究结果证实内源性AnxA1可调控真菌感染期间中性粒细胞的免疫应答，以及其脂质膜结构组织与代谢过程。