A multifunctional glycoprotein, osteopontin (OPN), can modulate the function of macrophages, resulting in either protective or deleterious effects in various inflammatory diseases and infection in the lungs. Although macrophages play the critical roles in mediating host defenses against cryptococcosis or cryptococcal pathogenesis, the involvement of macrophage-derived OPN in pulmonary infection caused by fungus Cryptococcus has not been elucidated. Thus, our current study aimed to investigate the contribution of OPN to the regulation of host immune response and macrophage function using a mouse model of pulmonary cryptococcosis. We found that OPN was predominantly expressed in alveolar macrophages during C. neoformans infection. Systemic treatment of OPN during C. neoformans infection resulted in an enhanced pulmonary fungal load and an early onset of type 2 inflammation within the lung, as indicated by the increase of pulmonary eosinophil infiltration, type 2 cytokine production, and M2-associated gene expression. Moreover, CRISPR/Cas9–mediated OPN knockout murine macrophages had enhanced ability to clear the intracellular fungus and altered macrophage phenotype from pathogenic M2 to protective M1. Altogether, our data suggested that macrophage-derived OPN contributes to the elaboration of C. neoformans–induced type 2 immune responses and polarization of M2s that promote fungal survival and proliferation within macrophages.

多功能糖蛋白骨桥蛋白 (OPN) 可以调节巨噬细胞的功能，在各种炎症性疾病和肺部感染中产生保护或有害作用。尽管巨噬细胞在介导宿主防御隐球菌病或隐球菌发病机制方面发挥关键作用，但尚未阐明巨噬细胞来源的 OPN 参与由真菌隐球菌引起的肺部感染。因此，我们目前的研究旨在使用肺隐球菌病小鼠模型研究 OPN 对宿主免疫反应和巨噬细胞功能调节的贡献。我们发现 OPN 在新型念珠菌感染期间主要在肺泡巨噬细胞中表达。OPN 期间的全身治疗新型隐球菌感染导致肺部真菌负荷增加和肺内 2 型炎症的早期发作，表现为肺嗜酸性粒细胞浸润、2 型细胞因子产生和 M2 相关基因表达的增加。此外，CRISPR/Cas9 介导的 OPN 敲除小鼠巨噬细胞清除细胞内真菌的能力增强，并将巨噬细胞表型从致病性 M2 改变为保护性 M1。总而言之，我们的数据表明，巨噬细胞衍生的 OPN 有助于形成新型 C.neoformans诱导的 2 型免疫反应和 M2 的极化，从而促进巨噬细胞内的真菌存活和增殖。