MMPs, Integrins and Microglial activation in HAND

HAND 中的 MMP、整合素和小胶质细胞激活

• 批准号: 8447415
• 负责人: Katherine E Conant
• 金额: $ 18.6万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-21 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8447415
• 关键词: Area; Biological Assay; Brain; Cadherins; Cell Adhesion Molecules; Cell surface; Cells; Cerebrospinal Fluid; Co-Immunoprecipitations; Data; Demyelinations; Disease; Disease model; Encephalitis; Goals; Grant; HIV; HIV Envelope Protein gp120; Immunoglobulin Domain; Immunologic Deficiency Syndromes; In Vitro; Inflammatory; Inhibition of Matrix Metalloproteinases Pathway; Injury; Integrin Binding; Integrins; Ligands; Ligation; Link; Lipopolysaccharides; Macrophage-1 Antigen; Mass Spectrum Analysis; Matrix Metalloproteinase Inhibitor; Matrix Metalloproteinases; Measures; Mediating; Microglia; Midbrain structure; Minocycline; Molecular; Morphology; Neuronal Injury; Neurons; Patients; Peptide Hydrolases; Phagocytosis; Phenotype; Play; Production; Proteins; Publications; Publishing; Reactive Oxygen Species; Role; Sampling; Signal Transduction; Stimulus; Synapses; TNF gene; Techniques; Testing; Transgenic Animals; Virus Diseases; base; cell fixing; cell type; clinically relevant; dopaminergic neuron; in vivo; intercellular cell adhesion molecule; interest; migration; nervous system disorder; neurotoxicity; protein protein interaction; receptor; research study; response; single molecule

DESCRIPTION (provided by applicant): Classical microglial activation may contribute to neuronal injury occurring with HIV associated neurological disorders (HAND). Emerging evidence suggests that matrix metalloproteinases (MMPs) could play a critical role in stimulating such activation. For example, inhibition of MMP activity blocks microglial activation in response to stimuli including lipopolysaccharide. In addition, minocycline, a potent inhibitor of MMP expression and activity, abrogates microglial activation occurring with osmotic demyelination as well as with simian immunodeficiency viral (SIV) infection. The mechanisms by which MMPs might activate microglia are not completely understood. Of interest, however, is the potential for MMPs to generate ligands for integrins that are highly expressed on microglia. Integrin dependent signaling can in turn stimulate changes associated with an activated phenotype. That this mechanism could be important is underlined by data showing that inhibition of microglial integrin expression, or function, blocks microglial phagocytosis and migration. In addition, recent studies have shown that select integrin antagonists can substantially reduce microglial activation and associated neurotoxicity in more than one disease model. In previous publications we have shown that HIV proteins can increase MMP release from brain derived cells, and that MMP levels are increased in spinal fluid samples from patients with HAND. In the present application, we hypothesize that these MMPs generate specific cell adhesion molecule (CAM) fragments that will in turn engage microglial integrins. Our focus on CAM fragments is based on several considerations. CAMs are easily accessible by virtue of their proximity to the cell surface, an area where MMP activity may be concentrated. We and others have shown that MMPs stimulate ectodomain shedding of these molecules, and elevated levels of soluble forms can be detected in spinal fluid samples from patients with brain inflammation. Moreover, we have recently published data showing that the shed domain of at least one CAM can interact with a microglial integrin that has been well linked to an activated phenotype. In the present R21 proposal we plan to identify microglial integrin-binding ligands that may be increased in association with HIV, to investigate the hypothesis that these ligands stimulate classical, pro-inflammatory microglial activation, and to determine whether this activation is of sufficient magnitude to be inimical to vulnerable neurons. We will focus on CAMs that are widely expressed in the CNS, including the immunoglobulin (Ig) domain containing intercellular cell adhesion molecules (ICAMs) and synaptic CAMs (synCAMs), as well as the cadherins. We will also focus on integrins that mediate microglial activation in other disease models, such as LFA-1 and Mac- 1. This dual PI grant relies on expertise related to MMPs (KC), as well as microglia and dopaminergic neurons (KMZ). The possibility that MMPs contribute to microglial activation in the setting of HIV is yet untested and clinically relevant, in that it would allow MMP inhibitor to be used in an attempt to reduce such activation. Further study of the receptors that underlie MMP dependent effects is also clinically relevant. At least one soluble CAM can interact with LFA-1, a microglial integrin for which a clinically tolerable antagonist has been developed.

描述（由申请人提供）：经典的小胶质细胞激活可能导致HIV相关神经系统疾病（HAND）发生的神经元损伤。新出现的证据表明，基质金属蛋白酶（MMPs）可能在刺激这种激活中发挥关键作用。例如，抑制MMP活性可阻断小胶质细胞对包括脂多糖在内的刺激的激活。此外，米诺环素是一种有效的MMP表达和活性抑制剂，可以消除渗透性脱髓鞘和猿猴免疫缺陷病毒（SIV）感染时发生的小胶质细胞激活。MMPs激活小胶质细胞的机制尚不完全清楚。然而，令人感兴趣的是MMPs产生整合素配体的潜力，这些配体在小胶质细胞上高度表达。整合素依赖的信号传导反过来可以刺激与活化表型相关的变化。数据显示，抑制小胶质整合素的表达或功能，可阻断小胶质细胞的吞噬和迁移，这一机制可能很重要。此外，最近

项目成果

Soluble ICAM-5, a product of activity dependent proteolysis, increases mEPSC frequency and dendritic expression of GluA1.

• DOI: 10.1371/journal.pone.0069136
• 发表时间: 2013
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Lonskaya I;Partridge J;Lalchandani RR;Chung A;Lee T;Vicini S;Hoe HS;Lim ST;Conant K
• 通讯作者: Conant K