Regulation of monocyte recruitment and function by the IL-23/IL-17 axis

描述（由申请人提供）：单核增生李斯特菌（LM）是一种细胞内细菌，可导致孕妇自然流产，并可导致免疫功能低下个体败血症和脑膜炎。对LM和其他病原体的先天免疫是由中性粒细胞、单核细胞和巨噬细胞提供的。单核细胞是骨髓来源的髓样细胞，在外周血中循环，直到被动员到组织中。常驻单核细胞产生组织巨噬细胞和树突状细胞，而炎性单核细胞提供抗感染保护，但在癌症和其他自身免疫性/炎症性疾病中也可能有害。我们发表的数据显示，细胞因子IL-23以及IL- 17a和IL- 17f的受体（IL- 17RA）是抵抗LM感染所必需的。我们现在已经确定IL-23是LM感染期间单核细胞募集的最佳条件。基于这些已发表的数据和我们的新观察，我们假设IL-23/IL-17轴在系统性LM感染期间调节单核细胞的募集和功能。利用缺乏IL-23， IL-17RA， IL-17A和IL-17F的小鼠的各种体内和体外方法将专门解决以下目标。特异性Aim 1将确定IL-23/IL-17轴在LM感染期间如何调节单核细胞募集。缺乏IL-23、IL- 17ra、IL- 17A和IL- 17f的小鼠将被用来确定这些分子在LM感染前和感染期间如何影响单核细胞募集。此外，这些细胞因子对单核细胞募集趋化因子的直接和间接影响将被确定。特异性Aim 2将确定IL-23/IL-17轴在LM感染期间如何增强单核细胞功能。IL-23/IL-17轴对最佳单核细胞效应功能的需求和充分性将通过测量保护LM所需的单核细胞效应分子来确定。从这些研究中获得的数据可能会导致在感染和其他疾病状态下调节单核细胞功能的治疗选择。

DESCRIPTION (provided by applicant): Listeria monocytogenes (LM) is an intracellular bacterium that can cause spontaneous abortions in pregnant women and can lead to septicemia and meningitis in immunocompromised individuals. Innate immunity to LM and other pathogens is provided by neutrophils, monocytes and macrophages. Monocytes are bone marrow derived myeloid cells that circulate in the peripheral blood until being mobilized into tissues. Resident monocytes give rise to tissue macrophages and dendritic cells, while inflammatory monocytes provide protection against infections but can also be detrimental during cancer and other autoimmune/inflammatory diseases. Our published data have revealed that the cytokine IL-23 and the receptor for IL-17A and IL-17F (IL- 17RA) are required for protection against LM infection. We have now established that IL-23 is required for optimal monocyte recruitment during LM infection. Based upon these published data and our novel observations, we hypothesize that the IL-23/IL-17 axis regulates the recruitment and function of monocytes during systemic LM infection. A variety of in vivo and in vitro approaches utilizing mice lacking IL-23, IL-17RA, IL-17A, and IL-17F will specifically address the following aims. Specific Aim 1 will determine how the IL-23/IL-17 axis regulates monocyte recruitment during LM infection. Mice lacking IL-23, IL-17RA, IL- 17A, and IL-17F will be utilized to determine how these molecules influence monocyte recruitment before, and during, LM infection. Furthermore, the direct and indirect impact of these cytokines on monocyte recruiting chemokines will be determined. Specific Aim 2 will determine how the IL-23/IL-17 axis enhances monocyte function during LM infection. The requirement and sufficiency of the IL-23/IL-17 axis for optimal monocyte effector functions will be determined by measuring monocyte effector molecules that are required for protection against LM. The data obtained from these studies may lead to therapeutic options aimed at regulating monocyte function during infectious and other disease states.