Cryptococcus neoformans (C. neoformans) is an important opportunistic fungal pathogen for pulmonary cryptococcosis. Previously, we demonstrated that CD146 mediated the adhesion of C. neoformans to the airway epithelium. CD146 is more than an adhesion molecule. In the present study, we aimed to explore the roles of CD146 in the inflammatory response in pulmonary cryptococcosis. CD146 was decreased in lung tissues from patients with pulmonary cryptococcosis. Similarly, C. neoformans reduced pulmonary CD146 expression in mice following intratracheal inoculation. To explore the pathological roles of CD146 reduction in pulmonary cryptococcosis, CD146 knockout (KO) mice were inoculated with C. neoformans via intratracheal instillation. CD146 deficiency aggravated C. neoformans infection, as evidenced by a shortened survival time and increased fungal burdens in the lung. Inflammatory type 2 cytokines (IL-4, IL-5, and TNF-α) and alternatively activated macrophages were increased in the pulmonary tissues of CD146 KO-infected mice. CD146 is expressed in immune cells (macrophages, etc.) and nonimmune cells, i.e., epithelial cells and endothelial cells. Bone marrow chimeric mice were established and infected with C. neoformans. CD146 deficiency in immune cells but not in nonimmune cells increased fungal burdens in the lung. Mechanistically, upon C. neoformans challenge, CD146 KO macrophages produced more neutrophil chemokine KC and inflammatory cytokine TNF-α. Meanwhile, CD146 KO macrophages decreased the fungicidity and production of reactive oxygen species. Collectively, C. neoformans infection decreased CD146 in pulmonary tissues, leading to inflammatory type 2 responses, while CD146 deficiency worsened pulmonary cryptococcosis.

新型隐球菌（C. neoformans）是肺隐球菌病的重要机会性真菌病原体。之前，我们证明 CD146 介导新型隐球菌与气道上皮的粘附。CD146 不仅仅是一种粘附分子。在本研究中，我们旨在探讨CD146在肺隐球菌病炎症反应中的作用。肺隐球菌病患者肺组织中 CD146 减少。同样，气管内接种后，新型隐球菌降低了小鼠肺部 CD146 的表达。为了探讨 CD146 减少在肺隐球菌病中的病理作用，通过气管内滴注给 CD146 敲除 (KO) 小鼠接种新型隐球菌。CD146 缺乏会加重新型隐球菌感染，生存时间缩短和肺部真菌负担增加就证明了这一点。CD146 KO 感染小鼠的肺组织中炎症性 2 型细胞因子（IL-4、IL-5 和 TNF-α）和替代激活的巨噬细胞增加。CD146在免疫细胞(巨噬细胞等)和非免疫细胞，即上皮细胞和内皮细胞中表达。建立骨髓嵌合小鼠并感染新型隐球菌。免疫细胞中的 CD146 缺陷（而非非免疫细胞中的 CD146 缺陷）会增加肺部的真菌负担。从机制上讲，在新型隐球菌攻击后，CD146 KO巨噬细胞产生更多的中性粒细胞趋化因子 KC 和炎症细胞因子 TNF-α。同时，CD146 KO巨噬细胞降低了杀菌力和活性氧的产生。总的来说，新型隐球菌感染降低了肺组织中的 CD146，导致 2 型炎症反应，而 CD146 缺乏则使肺隐球菌病恶化。