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

描述(由申请人提供)：单核细胞增生性李斯特菌(Lm)是一种细胞内细菌，可导致孕妇自然流产，并可导致免疫功能受损的人发生败血症和脑膜炎。对LM和其他病原体的天然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系细胞，它在外周血中循环，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预防感染的保护，但在癌症和其他自身免疫/炎症性疾病中也可能是有害的。我们已发表的数据表明，细胞因子IL-23以及IL-17A和IL-17F受体(IL-17RA)是抵抗LM感染所必需的。我们现在已经确定，在LM感染过程中，IL-23是单核细胞最佳募集所必需的。基于这些已发表的数据和我们新的观察结果，我们假设IL-23/IL-17轴调节系统性LM感染过程中单核细胞的招募和功能。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具体解决以下目标。具体目标1将确定IL-23/IL-17轴如何在LM感染过程中调节单核细胞募集。缺乏IL-23、IL-17RA、IL-17A和IL-17F的小鼠将被用来确定这些分子是如何在感染之前和期间影响单核细胞募集的。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。具体目标2将确定IL-23/IL-17轴如何在LM感染过程中增强单核细胞功能。IL-23/IL-17轴对最佳单核细胞效应器功能的需求和充分性将通过测量单核细胞效应器分子来确定，单核细胞效应器分子是抵抗LM所需的。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下单核细胞功能的治疗选择。 公共卫生相关性：完成这项提议后产生的数据将导致详细了解细胞因子(IL-23/IL-17)如何在系统感染期间调节单核细胞的功能。这一知识将允许更有效的疫苗生成，并导致在包括癌症、自身免疫和感染在内的不同疾病状态下增强或限制单核细胞功能的策略。

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. PUBLIC HEALTH RELEVANCE: Data generated upon completion of this proposal will result in a detailed understanding of how cytokines (IL- 23/IL-17) regulate the function of monocytes during systemic infection. This knowledge will allow for more effective vaccine generation and lead to strategies to either enhance or limit monocyte function during different disease states including cancer, autoimmunity, and infection.