Shirey Kari Ann, Lai Wendy, Pletneva Lioubov M, Finkelman Fred D, Feola David J, Blanco Jorge C G, Vogel Stefanie N
Department of Microbiology and Immunology, University of Maryland, School of Medicine, Baltimore, Maryland, USA;
Sigmovir Biosystems, Inc., Rockville, Maryland, USA;
J Leukoc Biol. 2014 Dec;96(6):951-5. doi: 10.1189/jlb.4HI0414-226R. Epub 2014 Jul 9.
RSV is the most significant cause of serious lower respiratory tract infection in infants and young children worldwide. There is currently no vaccine for the virus, and antiviral therapy (e.g., ribavirin) has shown no efficacy against the disease. We reported that alternatively activated macrophages (AAMs) mediate resolution of RSV-induced pathology. AAM differentiation requires macrophage-derived IL-4 and -13, autocrine/paracrine signaling through the type I IL-4 receptor, and STAT6 activation. Based on these findings, we reasoned that it would be possible to intervene therapeutically in RSV disease by increasing AAM differentiation, thereby decreasing lung pathology. Mice treated with the IL-4/anti-IL-4 immune complexes, shown previously to sustain levels of circulating IL-4, increased the RSV-induced AAM markers arginase-1 and mannose receptor and decreased the lung pathology. Induction of PPARγ, shown to play a role in AAM development, by the PPARγ agonist rosiglitazone or treatment of mice with the macrolide antibiotic AZM, also reported to skew macrophage differentiation to an AAM phenotype, increased the AAM markers and mitigated RSV-induced lung pathology. Collectively, our data suggest that therapeutic manipulation of macrophage differentiation to enhance the AAM phenotype is a viable approach for ameliorating RSV-induced disease.
呼吸道合胞病毒（RSV）是全球婴幼儿严重下呼吸道感染的最主要病因。目前尚无针对该病毒的疫苗，抗病毒治疗（如利巴韦林）对该疾病也无疗效。我们曾报道，交替活化的巨噬细胞（AAM）介导RSV诱导的病理反应的消退。AAM分化需要巨噬细胞衍生的IL-4和-13、通过I型IL-4受体的自分泌/旁分泌信号传导以及STAT6激活。基于这些发现，我们推断通过增加AAM分化、从而减轻肺部病理反应，有可能对RSV疾病进行治疗干预。用IL-4/抗IL-4免疫复合物处理的小鼠，先前已证明该复合物可维持循环IL-4水平，其RSV诱导的AAM标志物精氨酸酶-1和甘露糖受体增加，肺部病理反应减轻。PPARγ激动剂罗格列酮诱导PPARγ（已证明其在AAM发育中起作用），或用大环内酯类抗生素阿奇霉素处理小鼠（也报道其可使巨噬细胞分化偏向AAM表型），均可增加AAM标志物并减轻RSV诱导的肺部病理反应。总体而言，我们的数据表明，通过治疗性调控巨噬细胞分化以增强AAM表型，是改善RSV诱导疾病的一种可行方法。
