ANXA1 down regulates IL-1b

Cutaneous leishmaniasis (CL) is characterized by severe local inflammation, predominantly mediated by IL-1β, TNF, and cytotoxicity, mediators associated with tissue damage and lesion development. Given the high rate of therapeutic failure in <i>Leishmania braziliensis</i> infection, the investigation of molecules that regulate inflammatory response, is an adjuvant therapeutical strategy. Here we investigated the effects of Annexin A1 (ANXA1) on the inflammatory response of CL patients. <i>I</i><i>n silico</i> analyses from our previous transcriptome databases showed increased expression of <i>ANXA1</i>, <i>IL1B</i>, and <i>IL10</i> genes in skin biopsies from CL patients when compared to healthy skin from healthy subjects (HS). Also, increased levels of <i>ANXA1</i>, <i>IL1B</i>, and <i>IL10</i> proteins were observed in serum and cultures of skin biopsies in CL patients when compared to HS. The treatment of lesion biopsies with recombinant ANXA1 reduced IL-1β levels without affecting IL-10, indicating a selective anti-inflammatory effect. Additionally, monocyte-derived macrophages from HS produced high levels of ANXA1, IL-1β, and IL-10 upon <i>Leishmania</i> infection. Blockade of FPR2 receptor increased ANXA1 levels. Finally, addition of recombinant ANXA1 to macrophages did not affects the ability of these cells to kill <i>Leishmania</i>. Our findings demonstrate that ANXA1 negatively regulates IL-1β in CL, without impairing anti-inflammatory mechanisms or macrophage microbicidal activity.

皮肤利什曼病（Cutaneous leishmaniasis，CL）的特征是严重的局部炎症，主要由IL-1β、TNF及细胞毒性介导，这些介质与组织损伤和病灶发展相关。鉴于巴西利什曼原虫（Leishmania braziliensis）感染的治疗失败率较高，研究调控炎症反应的分子是一种辅助治疗策略。本研究探讨了膜联蛋白A1（Annexin A1，ANXA1）对CL患者炎症反应的影响。通过对前期转录组数据库的计算机模拟分析（in silico）发现，与健康受试者（healthy subjects，HS）的健康皮肤相比，CL患者皮肤活检样本中ANXA1、IL1B和IL10基因的表达显著升高。此外，CL患者血清及皮肤活检培养物中ANXA1、IL1B和IL10蛋白水平较HS显著升高。用重组膜联蛋白A1处理病灶活检样本可降低IL-1β水平而不影响IL-10，表明其具有选择性抗炎作用。此外，HS来源的单核细胞衍生巨噬细胞在感染利什曼原虫后会产生高水平的ANXA1、IL-1β和IL-10。阻断FPR2受体可提高ANXA1水平。最后，向巨噬细胞中添加重组膜联蛋白A1不会影响这些细胞杀死利什曼原虫的能力。我们的研究结果表明，ANXA1在CL中负调控IL-1β，且不损害抗炎机制或巨噬细胞的杀菌活性。