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

描述（由申请方提供）：单核细胞增生李斯特菌（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和其他病原体的天然免疫由中性粒细胞、单核细胞和巨噬细胞提供。单核细胞是骨髓来源的髓样细胞，其在外周血中循环直到被动员到组织中。驻留的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针对感染的保护，但在癌症和其他自身免疫性/炎性疾病期间也可能是有害的。我们已发表的数据表明，细胞因子IL-23和IL-17 A和IL-17 F受体（IL-17 RA）是预防LM感染所必需的。我们现在已经确定IL-23是LM感染期间最佳单核细胞募集所必需的。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轴调节全身LM感染期间单核细胞的募集和功能。利用缺乏IL-23、IL-17 RA、IL-17 A和IL-17 F的小鼠的多种体内和体外方法将具体地解决以下目的。具体目标1将确定IL-23/IL-17轴如何调节LM感染期间单核细胞募集。将利用缺乏IL-23、IL-17 RA、IL-17 A和IL-17 F的小鼠来确定这些分子在LM感染之前和期间如何影响单核细胞募集。此外，将确定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。特异性目的2将确定IL-23/IL-17轴如何在LM感染期间增强单核细胞功能。IL-23/IL-17轴对于最佳单核细胞效应子功能的需求和充分性将通过测量针对LM的保护所需的单核细胞效应子分子来确定。从这些研究中获得的数据可能会导致旨在调节感染和其他疾病状态期间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.